JP6019015B2 - Method for treating hematological malignancies using 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone - Google Patents

Description

(Cross-reference of related applications)
This application claims the priority of US Provisional Application No. 61 / 350,438, filed June 1, 2010, the disclosure of which is incorporated herein by reference in its entirety. ing.

(Technical field)
Drug-resistant hematological malignancy in a subject, comprising administering to the subject a therapeutically effective amount of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutical salt or solvate thereof Methods of treating are provided herein.

(background)
Hematologic or hematopoietic malignancies are blood or bone marrow cancers, including leukemias and lymphomas. Leukemia is characterized by uncontrolled accumulation of blood cells, which are classified into type 4: acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic bone marrow Sexual leukemia (CML). Acute leukemia is a rapidly progressive disease that results in the accumulation of immature, nonfunctional cells in the bone marrow and blood. This bone marrow often stops the formation of sufficient normal red blood cells, white blood cells and platelets. On the other hand, chronic leukemia progresses more slowly and allows the formation of a larger number of more mature functional cells. Chronic leukemia accounts for 11% more cases than acute leukemia.

  In 2009, it was estimated that 245,225 people in the United States suffered from leukemia and were alive or in remission. In 2009, leukemia was expected to attack adults more than 10 times more than children (approximately 44,790 adults compared to 3,509 children aged 0-14 years). The most common leukemia types in adults are acute myeloid leukemia (AML) estimated to be 12,810 new cases in 2009 and chronic lymphocytic leukemia (CLL) estimated to be about 15,490 new cases in 2009 is there. Chronic myeloid leukemia (CML) was estimated to affect approximately 5,050 people in 2009. The most common leukemia type in children is acute lymphoblastic leukemia (ALL), which was estimated to affect approximately 5,760 people in 2009.

  Current chemotherapy can produce complete remission, but long-term disease-free survival of leukemia, especially AML, is low. For example, AML survival was estimated to be less than about 20% in 2009. Thus, there is a clear and unmet need for effective therapies for the treatment of hematological malignancies including leukemia.

(Outline of disclosure)
Drug-resistant hematological malignancy in a subject comprising administering to the subject a therapeutically effective amount of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutical salt or solvate thereof Methods of treating are provided herein. In some embodiments, the drug resistant hematologic malignancy is not imatinib-resistant CML.

  In one embodiment, the drug resistant hematologic malignancy is a drug resistant leukemia, provided that the leukemia is not imatinib-resistant CML.

In another embodiment, the leukemia is resistant to a Bcr-Abl kinase inhibitor, provided that the leukemia is not imatinib-resistant CML. In some embodiments, the leukemia is resistant to imatinib, dasatinib, nilotinib , or bosutinib, provided that the leukemia is not imatinib-resistant CML. In some embodiments, the leukemia is resistant to cytarabine. In some embodiments, the leukemia is resistant to vincristine. In some embodiments, the drug resistant leukemia is Philadelphia positive. In some embodiments, the drug resistant leukemia is relapsed or refractory.

In yet another embodiment, the leukemia is drug resistant acute leukemia. In some embodiments, the acute leukemia is resistant to a Bcr-Abl kinase inhibitor. In some embodiments, the acute leukemia is resistant to imatinib, dasatinib, nilotinib , or bosutinib. In some embodiments, the acute leukemia is resistant to cytarabine. In some embodiments, the acute leukemia is resistant to vincristine. In some embodiments, the drug resistant acute leukemia is Philadelphia positive. In some embodiments, the drug resistant acute leukemia is relapsed or refractory.

In yet another embodiment, the drug resistant acute leukemia is drug resistant ALL. In some embodiments, ALL is resistant to a Bcr-Abl kinase inhibitor. In some embodiments, ALL is resistant to imatinib, dasatinib, nilotinib , or bosutinib. In some embodiments, ALL is resistant to cytarabine. In some embodiments, ALL is resistant to vincristine. In some embodiments, the drug resistant ALL is Philadelphia positive. In some embodiments, the drug resistant ALL is relapsed or refractory.

In yet another embodiment, the drug resistant acute leukemia is drug resistant AML. In some embodiments, AML is resistant to Bcr-Abl kinase inhibitors. In some embodiments, the AML is resistant to imatinib, dasatinib, nilotinib , or bosutinib. In some embodiments, AML is resistant to cytarabine. In some embodiments, AML is resistant to vincristine. In some embodiments, the drug resistant AML is Philadelphia positive. In some embodiments, the drug resistant AML is relapsed or refractory.

In yet another embodiment, the drug resistant leukemia is a drug resistant chronic leukemia, provided that the leukemia is not imatinib-resistant CML. In some embodiments, the chronic leukemia is resistant to a Bcr-Abl kinase inhibitor, provided that the chronic leukemia is not imatinib-resistant CML. In some embodiments, the chronic leukemia is resistant to imatinib, dasatinib, nilotinib , or bosutinib, provided that the chronic leukemia is not imatinib-resistant CML. In some embodiments, the chronic leukemia is resistant to cytarabine. In some embodiments, the chronic leukemia is resistant to vincristine. In some embodiments, the drug resistant chronic leukemia is Philadelphia positive. In some embodiments, the drug resistant chronic leukemia is relapsed or refractory.

In yet another embodiment, the drug resistant chronic leukemia is a drug resistant CLL. In some embodiments, the CLL is resistant to a Bcr-Abl kinase inhibitor. In some embodiments, the CLL is resistant to imatinib, dasatinib, nilotinib , or bosutinib. In some embodiments, the CLL is resistant to cytarabine. In some embodiments, the CLL is resistant to vincristine. In some embodiments, the drug resistant CLL is Philadelphia positive. In some embodiments, the drug resistant CLL is relapsed or refractory.

In yet another embodiment, the drug resistant chronic leukemia is drug resistant CML provided that the CML is not imatinib-resistant. In some embodiments, the CML is resistant to Bcr-Abl kinase inhibitors provided that the CML is not imatinib-resistant. In some embodiments, the CML is resistant to dasatinib, nilotinib , or bosutinib. In some embodiments, the CML is resistant to cytarabine. In some embodiments, the CML is resistant to vincristine. In some embodiments, the drug resistant CML is Philadelphia positive. In some embodiments, the drug resistant CML is relapsed or refractory.

  6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof, at a dose of about 2, about 5, about 10, about 15, or about 20 mg / kg / day Also provided herein is a method of treating leukemia in a subject comprising orally administering to the subject. In one embodiment, the leukemia is drug resistant.

  In addition, 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutical salt or solvate thereof, is intravenously administered to a subject in a dose range of about 0.01 to about 10 mg / kg / day. Also provided herein is a method of treating leukemia in a subject. In one embodiment, the leukemia is drug resistant.

  6-Cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof, of 6-cyclohexyl-1-hydroxy, which ranges from about 1 to about 20 μM at steady state. Provided herein is a method of treating leukemia in a subject comprising administering an amount sufficient to provide a plasma concentration of -4-methyl-2 (1H) -pyridone. In one embodiment, the leukemia is drug resistant.

  6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof, of 6-cyclohexyl-1-hydroxy-4-4 ranging from about 1 to about 50 μM. Provided herein is a method of treating leukemia in a subject comprising administering an amount sufficient to provide a maximum plasma concentration of methyl-2 (1H) -pyridone. In one embodiment, the leukemia is drug resistant.

  6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof, of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone Sufficient to provide a maximum plasma concentration of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone that ranges from about 1 to about 50 μM when two or more doses are administered Provided herein is a method of treating leukemia in a subject comprising administering a suitable amount. In one embodiment, the leukemia is drug resistant.

  A method for inhibiting the growth of leukemic stem cells comprising the step of contacting 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutical salt or solvate thereof, with a cell. Provide in the letter. In one embodiment, the leukemia stem cell is drug resistant.

(Brief description of the drawings)
Figure 1 shows the effect of cytarabine on KG-1a cancer cell line after 72 hours treatment, where cytarabine is about 0.625 μM for cytarabine-non-resistant KG-1a and cytarabine-resistant KG-1aCR With an IC ₅₀ value of about 20 μM.

FIG. 2 shows the effect on the KG-1a cancer cell line after 72 hours treatment with 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone (CPX), where CPX is cytarabine- It has an IC ₅₀ value of 2 μM for non-resistant KG-1a and about 6 μM for cytarabine-resistant KG-1aCR.

FIG. 3 shows the effect of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone (CPX) on Nalm-6 cancer cell line after 72 hours treatment, where Nalm-6 VR is A vincristine resistant cell line, wherein vincristine has an IC ₅₀ value of about 1 nM for vincristine-non-resistant Nalm-6 and about 32 nM for vincristine-resistant Nalm-6 VR.

(Detailed explanation)
In order to facilitate an understanding of the disclosure provided herein, a number of terms are defined below.

  In general, the nomenclature used herein and the experimental techniques in organic chemistry, medicinal chemistry, and pharmacology described herein are well known and commonly used in the art. . Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

  The term “subject” refers to an animal including, but not limited to, primates (eg, humans), cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms “subject” and “patient” are used interchangeably herein, eg, with respect to a mammalian subject, such as a human subject, and in one embodiment with respect to a human.

  The terms “treat”, “treating” and “treatment” alleviate or inhibit a disorder, disease or condition or one or more symptoms associated with the disorder, disease or condition; Alternatively, it is meant to include alleviating or eradicating the cause of the disorder, disease or condition itself.

  The terms “prevent”, “preventing” and “prevention” refer to a method of delaying and / or eliminating the onset of a disorder, disease or condition and / or its associated symptoms; Or a method of reducing a subject's risk of acquiring a disorder, disease, or condition.

  The term “therapeutically effective amount” is an amount of a compound that, when administered, is sufficient to prevent or to some extent alleviate the onset of one or more symptoms of the disorder, disease, or condition being treated. Is included. The term “therapeutically effective amount” also refers to a biological molecule (eg, protein, enzyme, RNA, or DNA), cell, tissue, system, animal sought by a researcher, veterinarian, physician, or clinician. Or the amount of a compound that is sufficient to elicit a human biological or medical response.

  The term “pharmaceutically acceptable carrier”, “pharmaceutically acceptable excipient”, “physiologically acceptable carrier”, or “physiologically acceptable excipient” refers to a liquid or solid A pharmaceutically acceptable substance, composition, or vehicle, such as a filler, diluent, solvent, or encapsulating material. In one embodiment, each component is compatible with other components of the pharmaceutical formulation and is in excess of toxicity, irritation, allergic reaction, immunogenicity, or other issues that are commensurate with a reasonable benefit / risk ratio. Alternatively, it is “pharmaceutically acceptable” in the sense that it is suitable for use in contact with human and animal tissues or organs without complications. Remington, “The Science and Practice of Pharmacy”, 21st edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; “Handbook of Pharmaceutical Excipients”, 6th edition; edited by Rowe et al .; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; "Handbook of Pharmaceutical Additives", 3rd edition; edited by Ash and Ash; Gower Publishing Company: 2007; See Pharmaceutical Preformulation and Formulation, 2nd Edition; edited by Gibson; CRC Press LLC: Boca Raton, FL, 2009.

  The term “about” or “approximately” means a tolerance for a particular value determined by one of ordinary skill in the art, which depends in part on the way in which the value is measured or determined. In some embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In some embodiments, the term “about” or “approximately” means 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5% of a given value or range. , 4%, 3%, 2%, 1%, 0.5%, or 0.05%.

  The terms “active ingredient” and “active substance” are used alone or in combination with one or more pharmaceutically acceptable excipients to treat, prevent or ameliorate one or more symptoms of a condition, disorder or disease. Refers to a compound that is administered to a subject in combination. As used herein, “active ingredient” and “active substance” may be optically active isomers of the compounds described herein.

  The terms “drug”, “therapeutic agent”, and “chemotherapeutic agent” refer to a compound or their administration that is administered to a subject to treat, prevent or ameliorate one or more symptoms of a condition, disorder, or disease. Refers to a pharmaceutical composition.

  The term “solvate” refers to one or more molecules of a solute, eg, a compound provided herein, and one or more molecules of solvent present in a stoichiometric or non-stoichiometric amount. Refers to the complex or aggregate formed by. Suitable solvents include but are not limited to water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In some embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in crystalline form. In another embodiment, the complex or aggregate is in an amorphous form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

  The term “hematologic malignancy” refers to cancers of the body's blood-forming and immune systems—bone marrow and lymphoid tissues. Examples of hematological malignancies are, for example, myelodysplasia, lymphoma, leukemia, lymphoma (non-Hodgkin lymphoma), Hodgkin's disease (also referred to as Hodgkin lymphoma), and myeloma, eg acute lymphocytic leukemia (ALL), Acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophil leukemia (CNL), acute undifferentiated leukemia (AUL) ), Undifferentiated large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with AML (TM / TMDS) ), Mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative syndrome (MPD), and multiple myeloma (MM).

  The term “leukemia” refers to malignant neoplasms of hematopoietic tissue, including but not limited to chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myeloid leukemia and acute myeloblastic leukemia. Say. Leukemia recurs and can be refractory or resistant to conventional therapy.

  The term “relapsed” refers to a situation in which a subject or mammal having a cancer remission after treatment has cancer cell recovery.

  The term “refractory or resistant” refers to a situation in which a subject or mammal has cancer cells that remain in the body even after intensive treatment.

  The term “drug resistance” refers to a condition in which a disease does not respond to treatment with one or more drugs. Drug resistance is inherent meaning that the disease never reacts to one or more drugs, or an acquisition that means the disease becomes unresponsive to one or more drugs that have already reacted Can be either. In some embodiments, drug resistance is inherent. In some embodiments, drug resistance is obtained.

(Compound)
A compound suitable for use in the methods provided herein is 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically acceptable salt or solvate thereof, This is also known as ciclopirox and has the following structure:

  Ciclopirox is commercially available. Ciclopirox can be prepared, isolated or obtained by any method known to those skilled in the art. By way of example, ciclopirox can be prepared according to the methods described in US Pat. Nos. 3,883,545 and 3,972,888, the disclosures of each of which are incorporated herein by reference in their entirety.

  In one embodiment, the ciclopirox used in the methods provided herein is a free base. In one embodiment, the free base is a solid. In another embodiment, the free base is an amorphous form of a solid. In yet another embodiment, the free base is a crystalline form of a solid.

  In another embodiment, ciclopirox used in the methods provided herein is a pharmaceutically acceptable solvate of its free base. In one embodiment, the solvate is a hydrate.

  In yet another embodiment, ciclopirox used in the methods provided herein is magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide, L-arginine, venetamine, benzathine , Choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2- (diethylamino) -ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L -Lysine, morpholine, 4- (2-hydroxyethyl) -morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1- (2-hydroxyethyl) -pyrrolidine, pyridine, quinuclidine, quinoline, Including but not limited to phosphorus, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl) -1,3-propanediol, and tromethamine It is not a pharmaceutically acceptable salt.

  In some embodiments, the pharmaceutically acceptable salt is an inorganic salt of ciclopirox. In some embodiments, the pharmaceutically acceptable salt is an organic salt of ciclopirox. In some embodiments, the pharmaceutically acceptable salt is a primary amine salt of ciclopirox. In some embodiments, the pharmaceutically acceptable salt is a secondary amine salt of ciclopirox. In some embodiments, the pharmaceutically acceptable salt is a tertiary amine salt of ciclopirox. In some embodiments, the pharmaceutically acceptable salt is a quaternary amine salt of ciclopirox. In some embodiments, the pharmaceutically acceptable salt is an aliphatic amine salt of ciclopirox. In some embodiments, the pharmaceutically acceptable salt is an aromatic amine salt of ciclopirox. In some embodiments, the pharmaceutically acceptable salt is ciclopirox ethanolammonium.

(Pharmaceutical composition)
In one embodiment, a pharmaceutical composition comprising ciclopirox, or a pharmaceutically acceptable salt or solvate thereof, in combination with a pharmaceutically acceptable vehicle, carrier, diluent, excipient, or mixture thereof. Is provided herein.

  Pharmaceutical compositions containing ciclopirox can be formulated in various dosage forms for oral, parenteral and topical administration. Pharmaceutical compositions include delayed release, extended release, extended release, sustained release, pulsed release, controlled release, enhanced release, fast release, targeted release, programmed release dosage form, and gastric retention dosage form It can also be formulated as a modified release dosage form. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (Remington, “The Science and Practice of Pharmacy,” supra; Modified-Release Drug Delivery Technology, 2nd edition, edited by Rathbone et al., See Marcel Dekker, Inc .: New York, NY, 2008).

  In one embodiment, a pharmaceutical composition provided herein comprises ciclopirox, or a pharmaceutically acceptable salt or solvate thereof; and one or more pharmaceutically acceptable excipients or carriers. In a dosage form for oral administration.

  In another embodiment, the pharmaceutical composition provided herein comprises ciclopirox, or a pharmaceutically acceptable salt or solvate thereof; and one or more pharmaceutically acceptable excipients or carriers. It is formulated as a suspension for oral administration. In one embodiment, the suspensions provided herein include ciclopirox ethanolamine salts, as well as water, glycerin, sorbitol, sodium saccharin, xanthan gum, flavoring agents, citric acid, sodium citrate, methyl paraben, propyl paraben. And two or more excipients or carriers selected from the group consisting of potassium sorbate. In another embodiment, the suspension provided herein comprises ciclopirox ethanolamine salt, as well as water, glycerin, sorbitol, sodium saccharin, xanthan gum, flavoring agent, citric acid, sodium citrate, methyl paraben, propyl. Contains parabens and potassium sorbate. In yet another embodiment, the suspension provided herein consists of water, glycerin, sorbitol, sodium saccharin, xanthan gum, flavoring agent, citric acid, sodium citrate, methyl paraben, propyl paraben, and potassium sorbate. The solution contains 100 mg / L of ciclopirox.

  In yet another embodiment, the pharmaceutical composition provided herein comprises ciclopirox, or a pharmaceutically acceptable salt or solvate thereof; and one or more pharmaceutically acceptable excipients or carriers. Is formulated as a dosage form for parenteral administration. In one embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for intravenous administration. In another embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for subcutaneous administration. In yet another embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for intramuscular administration.

  In yet another embodiment, the pharmaceutical composition provided herein comprises ciclopirox, or a pharmaceutically acceptable salt or solvate thereof; and one or more pharmaceutically acceptable excipients or carriers. Formulated in a dosage form for topical administration.

  In yet another embodiment, the pharmaceutical composition provided herein comprises ciclopirox, or a pharmaceutically acceptable salt or solvate thereof; and one or more pharmaceutically acceptable excipients or carriers. Is formulated as a cream for topical administration. In one embodiment, the cream provided herein includes ciclopirox ethanolamine salt, as well as water, octyldodecanol, mineral oil, stearyl alcohol, cocamide DEA, polysorbate 60, myristyl alcohol, sorbitan monostearate, It contains two or more excipients or carriers selected from the group consisting of lactic acid and benzyl alcohol. In another embodiment, the cream provided herein comprises ciclopirox ethanolamine salt and water, octyldodecanol, mineral oil, stearyl alcohol, cocamide DEA, polysorbate 60, myristyl alcohol, sorbitan monostearate , Lactic acid, and benzyl alcohol. In yet another embodiment, the cream provided herein consists of water, octyldodecanol, mineral oil, stearyl alcohol, cocamide DEA, polysorbate 60, myristyl alcohol, sorbitan monostearate, lactic acid, and benzyl alcohol. 1 g of water miscible vanishing cream base contains 7.7 mg of ciclopirox.

  In yet another embodiment, the pharmaceutical composition provided herein comprises ciclopirox, or a pharmaceutically acceptable salt or solvate thereof; and one or more pharmaceutically acceptable excipients or carriers. Is formulated as a gel for topical administration. In one embodiment, the gel provided herein is selected from the group consisting of ciclopirox and water, isopropyl alcohol, octyldodecanol, dimethicone copolyol 190, carbomer 980, sodium hydroxide, and doxate sodium. Containing two or more excipients or carriers. In another embodiment, the gel provided herein comprises ciclopirox and water, isopropyl alcohol, octyldodecanol, dimethicone copolyol 190, carbomer 980, sodium hydroxide, and doxate sodium. In yet another embodiment, the gel provided herein is ciclopirox in 1 g of a gel consisting of water, isopropyl alcohol, octyldodecanol, dimethicone copolyol 190, carbomer 980, sodium hydroxide, and sodium doxate. Contains 7.7 mg.

  In yet another embodiment, the pharmaceutical composition provided herein comprises ciclopirox, or a pharmaceutically acceptable salt or solvate thereof; and one or more pharmaceutically acceptable excipients or carriers. Formulated as a shampoo for topical administration. In one embodiment, the shampoo provided herein comprises ciclopirox and two or more additives selected from the group consisting of water, sodium laureth sulfate, disodium laureth sulfosuccinate, sodium chloride, and laureth-2. Contains form or carrier. In another embodiment, the shampoo provided herein contains ciclopirox and water, sodium laureth sulfate, disodium laureth sulfosuccinate, sodium chloride, and laureth-2. In yet another embodiment, the shampoo provided herein contains 10 mg of ciclopirox in 1 g of a shampoo base consisting of water, sodium laureth sulfate, disodium laureth sulfosuccinate, sodium chloride, and laureth-2.

  In yet another embodiment, the pharmaceutical composition provided herein comprises ciclopirox, or a pharmaceutically acceptable salt or solvate thereof; and one or more pharmaceutically acceptable excipients or carriers. Formulated as a lacquer for topical administration. In one embodiment, the lacquer provided herein is selected from the group consisting of ciclopirox and butyl monoesters of poly (methyl vinyl ether / maleic acid) with ethyl acetate, isopropyl alcohol, and isopropyl alcohol as solvents. Containing two or more excipients or carriers. In another embodiment, the lacquer provided herein contains ciclopirox and a butyl monoester of poly (methyl vinyl ether / maleic acid) with ethyl acetate, isopropyl alcohol, and isopropyl alcohol as solvents. In yet another embodiment, the lacquer provided herein is in 1 g of a solution base consisting of ethyl acetate, isopropyl alcohol, and butyl monoester of poly (methyl vinyl ether / maleic acid) using isopropyl alcohol as a solvent. Contains 80 mg of ciclopirox.

  The pharmaceutical compositions provided herein can be provided in unit dosage forms or in repeated dosage forms. A unit dosage form as used herein refers to physically discrete units suitable for administration to human and animal subjects and individually packaged as is known in the art. Each unit dosage contains a predetermined amount of active ingredient that is sufficient to produce the desired therapeutic effect in association with the required pharmaceutical carrier or excipient. Examples of unit dosage forms include ampoules, syringes, and individually packaged tablets and capsules. Unit dosage forms may be administered in fractions or multiples thereof. A repeated dosage form is a plurality of identical unit dosage forms packaged in a single container that is administered in separate unit dosage forms. Examples of repetitive dosage forms include vials, tablets or capsule bottles, or pint bottles or gallon bottles.

  The pharmaceutical compositions provided herein can be administered once or multiple times at intervals of time. The exact dose and duration of treatment can vary with the age, weight and condition of the patient being treated and are determined empirically using known test protocols or by extrapolation from in vivo or in vitro tests or diagnostic data It is understood that it can be done. It is further understood that for any particular individual, the specific dosing schedule must be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration.

(A. Oral administration)
The pharmaceutical compositions provided herein for oral administration can be provided in solid, semi-solid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms are tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medical chewing gum, bulk powders, effervescent or Non-foaming powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups are included but are not limited to these. In addition to the active ingredient, the pharmaceutical composition includes, but is not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, anti-transfer agents, sweeteners Contains one or more pharmaceutically acceptable carriers or excipients, including flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and a carbon dioxide source be able to.

  The binder or granulating agent imparts cohesiveness to the tablet and ensures that the tablet remains intact after compression. Suitable binders or granulating agents include starches such as corn starch, potato starch, and pregelatinized starch (eg STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; acacia gum, alginic acid , Natural and synthetic rubbers such as alginates, tochaka extracts, panwar gum, gati gum, isagol shell skin mucus, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), veegum, larch arabogalactan, tragacanth powder, and guar gum Ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydro Cellulose such as cyclopropylmethylcellulose (HPMC); microcrystalline cellulose such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC, Marcus Hook, PA); and Including, but not limited to, mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. It is not something. The amount of binder or filler in the pharmaceutical compositions provided herein will vary depending on the type of formulation and can be readily identified by those skilled in the art. The binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.

  Suitable diluents include, but are not limited to, calcium hydrogen phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dried starch, and powdered sugar. . Some diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, can give some compressed tablets properties that allow disintegration in the mouth by chewing when present in sufficient amounts. Such compressed tablets can be used as chewable tablets. The amount of diluent in the pharmaceutical compositions provided herein will vary depending on the type of formulation and is readily identifiable by those skilled in the art.

  Suitable disintegrants include: agar; bentonite; cellulose, such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and veegum HV; crosslinks such as citrus pulp; Cellulose; Crosslinked polymer such as crospovidone; Crosslinked starch; Calcium carbonate; Microcrystalline cellulose such as sodium starch glycolate; Polacrilin potassium; Starch such as corn starch, potato starch, tapioca starch, and pregelatinized starch; Including, but not limited to, clays; algins; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein will vary depending on the type of formulation and is readily identifiable by those skilled in the art. The amount of disintegrant in the pharmaceutical compositions provided herein will vary depending on the type of formulation and is readily identifiable by those skilled in the art. The pharmaceutical compositions provided herein may contain from about 0.5 to about 15%, or from about 1 to about 5% by weight of disintegrant.

  Suitable lubricants include: calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycol such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; , Cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil, hydrogenated vegetable oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium; AEROSIL® 200 (WR Grace) , Baltimore, MD) and CAB-O-SIL® (Cabot, Boston, Mass.), And the like; and including but not limited to. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.

  Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O-SIL® (Cabot, Boston, MA), and asbestos-free talc. Suitable colorants include, but are not limited to, any approved certified water soluble FD & C dye, and water insoluble FD & C dye suspended on alumina hydrate, and lake pigment, and mixtures thereof. It is not a thing. A lake pigment is a combination of water-soluble dyes adsorbed on hydrated oxides of heavy metals, and these dyes are insoluble. Suitable flavoring agents include, but are not limited to, natural blends extracted from plants, such as fruits, and synthetic blends of compounds that produce a favorable taste, such as peppermint and methyl salicylate. Suitable sweeteners include, but are not limited to, sucrose, lactose, mannitol, syrup, glycerin, and artificial sweeteners such as saccharin and aspartam. Suitable emulsifiers are gelatin, gum acacia, tragacanth, bentonite, and polyoxyethylene sorbitan monooleate (e.g. TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (e.g. TWEEN® 80). And surfactants such as, but not limited to, triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, beegum, acacia gum, sodium carbomethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include but are not limited to glycerin, sorbitol, ethyl alcohol, and syrup. Examples of suitable non-aqueous liquids utilized in the emulsion include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric acid and tartaric acid. Suitable carbon dioxide sources include, but are not limited to, sodium bicarbonate and sodium carbonate.

  It should be understood that many carriers and excipients can perform several functions, even within the same formulation.

  Pharmaceutical compositions provided herein for oral administration are provided as compressed tablets, moist tablets, chewing licks, instant dissolving tablets, multilayer compressed tablets, or enteric coated tablets, dragees, or film coated tablets can do. Enteric coated tablets are compressed tablets that are coated with a substance that resists the action of gastric acid but dissolves or disintegrates in the intestine, thus protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar-coating that can be beneficial in shielding undesirable taste or odor and protecting the tablet from oxidation. Film-coated tablets are compressed tablets that are coated with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating provides the same general characteristics as sugar coating. Multi-layer compressed tablets are compressed tablets made by two or more compression cycles, including layered tablets and press-coated tablets or dry-coated tablets.

  The tablet dosage form is comprised of an active ingredient in powder, crystalline, or granular form, alone or including a binder, disintegrant, controlled release polymer, lubricant, diluent, and / or colorant. It can be prepared in combination with one or more carriers or excipients as described. Flavoring and sweetening agents are particularly useful in the manufacture of chewable tablets and lozenges.

  The pharmaceutical compositions provided herein for oral administration can be provided as soft or hard capsules that can be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFC), consist of two parts, one slips over the other, thus completely enclosing the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells such as gelatin shells that are plasticized by the addition of glycerin, sorbitol, or similar polyols. The soft gelatin shell may include a preservative to prevent microbial growth. Suitable preservatives are those described herein and include methyl and propylparaben, and sorbic acid. Liquid, semi-solid, and solid dosage forms provided herein may be encapsulated. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in US Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. Capsules may also be coated as known to those skilled in the art to alter or sustain dissolution of the active ingredient.

  The pharmaceutical compositions provided herein for oral administration can be provided in liquid and semi-solid dosage forms including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems, one of which is dispersed in the form of globules throughout another liquid and can be oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids or solvents, emulsifiers, and preservatives. Suspensions may include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcohol solutions include pharmaceutically acceptable acetals such as di (lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal; and water miscible solvents having one or more hydroxyl groups such as propylene glycol and ethanol May be included. An elixir is a clear, sweet aqueous alcoholic solution. A syrup is a concentrated aqueous solution of a sugar, such as sucrose, and may also contain a preservative. For liquid dosage forms, for example, polyethylene glycol as a solvent may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, so that it can be conveniently weighed for administration.

  Other useful liquid and semi-solid dosage forms include those containing the active ingredients provided herein, as well as 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene Glycol-550-dimethyl ether, including but not limited to dialkylated mono- or poly-alkylene glycols including polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 are: Refers to the approximate average molecular weight of polyethylene glycol. These formulations include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphate Can further comprise one or more antioxidants, such as, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamate.

  The pharmaceutical compositions provided herein for oral administration can also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in US Pat. No. 6,350,458.

  The pharmaceutical compositions provided herein for oral administration can be provided as non-foaming or foaming granules and powders for reconstitution into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-foamable granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and carbon dioxide sources.

  Coloring and flavoring agents can be used in all of the above dosage forms.

  The pharmaceutical compositions provided herein for oral administration include immediate release or modified release, including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release forms. It may be formulated as a dosage form.

(B. Parenteral administration)
The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implantation for local or systemic administration. As used herein, parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraureteral, intrasternal, intracranial, intramuscular, Includes intravesical administration, intravesical administration and subcutaneous administration.

  The pharmaceutical compositions provided herein for parenteral administration are in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and It can be formulated in solid form suitable for solution or suspension in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the pharmaceutical sciences (see, for example, Remington, “The Science and Practice of Pharmacy,” supra).

  Pharmaceutical compositions intended for parenteral administration include aqueous media, water-miscible media, non-aqueous media, antimicrobial agents or preservatives against microbial growth, stabilizers, solubility enhancers, isotonic agents, buffers, Antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickeners, pH adjustment Agents, and one or more pharmaceutically acceptable carriers and excipients, including but not limited to inert gases.

  Suitable aqueous media are water, saline, saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's. Injectable solution is included, but is not limited to these. Suitable non-aqueous media are non-volatile oils of plant origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, and coconut oil. Including but not limited to chain triglycerides and coconut seed oil. Suitable water miscible media are ethanol, 1,3-butanediol, liquid polyethylene glycols (eg, polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N, N-dimethyl. Including but not limited to acetamide and dimethyl sulfoxide.

  Suitable antibacterial or preservatives are phenol, cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoate, thimerosal, benzalkonium chloride (eg benzethonium chloride), methyl- and propyl-paraben, In addition, sorbic acid is included, but is not limited thereto. Suitable tonicity agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are those described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers are those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether 7-β-cyclodextrin (CAPTISOL®, CyDex Including, but not limited to, cyclodextrins.

  When the pharmaceutical compositions provided herein are formulated for repeated dose administration, the repeated dose parenteral formulation should contain an antimicrobial agent at a bacteriostatic or fungistatic concentration. All parenteral formulations must be sterile, as is known and practiced in the art.

  In one embodiment, pharmaceutical compositions for parenteral administration are provided as sterile solutions that can be used as such. In another embodiment, the pharmaceutical composition is provided as a sterilized dry soluble product comprising lyophilized powder and subcutaneous tablet to be reconstituted with vehicle prior to use. In yet another embodiment, the pharmaceutical composition is provided as a sterile suspension that can be used as is. In yet another embodiment, the pharmaceutical composition is provided as a sterilized dry insoluble product to be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is provided as a sterile emulsion that can be used as is.

  The pharmaceutical compositions provided herein for parenteral administration include immediate or modified forms including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release forms It can be formulated as a release dosage form.

  The pharmaceutical compositions provided herein for parenteral administration can be formulated as suspensions, solids, semi-solids, or thixotropic liquids for administration as implantable depots. In one embodiment, the pharmaceutical composition provided herein is in a solid inner matrix that is surrounded by an outer polymer membrane that is insoluble in bodily fluids but through which the active ingredients in the pharmaceutical composition can diffuse. Is distributed.

  Suitable inner matrices are polymethyl methacrylate, polybutyl-methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, Hydrophilic polymers such as ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrogels of acrylic and methacrylic esters, collagen, cross-linked polyvinyl alcohol, and cross-linked and partially hydrolyzed polyvinyl acetate However, it is not limited to these.

  Suitable outer polymer membranes are polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate, Includes vinylidene chloride, vinyl chloride copolymers with ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers However, it is not limited to these.

(C. Topical administration)
The pharmaceutical compositions provided herein can be administered topically to the skin, openings, or mucous membranes. Topical administration as used herein includes intradermal, intraconjunctival, intracorneal, intraocular, intraocular, intraaural, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.

  The pharmaceutical compositions provided herein include emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, bandages, elixirs, lotions, suspensions, tinctures, and plasters. Can be formulated in any dosage form suitable for topical or systemic administration, including foams, films, aerosols, irrigations, sprays, suppositories, bandages, and skin patches. Topical formulations of the pharmaceutical compositions provided herein can also include liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

  Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein are aqueous media, water miscible media, non-aqueous media, antimicrobial agents or preservatives against microbial growth, stabilization. Agents, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers , Cryoprotectants, lyoprotectants, thickeners, and inert gases.

  The pharmaceutical composition comprises electroporation, iontophoresis, phonophoresis, sonophoresis, or POWDERJECTTM (Chiron, Emeryville, CA), and BIOJECTTM (Bioject Medical Technologies, Tualatin, OR ) And the like, or can be administered locally by needle-free injection.

  The pharmaceutical compositions provided herein can be provided in the form of ointments, creams, and gels. Suitable ointment media are oily or hydrocarbon media, including lard, benzoic lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsified media or absorption such as hydrophilic petrolatum, hydroxystearin sulfate, and dehydrated lanolin Medium; water-removable medium such as hydrophilic ointment; water-soluble ointment medium containing polyethylene glycol of varying molecular weight; water-in-oil (W / O) containing cetyl alcohol, glyceryl monostearate, lanolin and stearic acid ) Emulsion media, either emulsions or oil-in-water (O / W) emulsions. (See Remington, “The Science and Practice of Pharmacy,” supra). These media are emollients but generally require the addition of antioxidants and preservatives.

  A suitable cream base can be oil-in-water or water-in-oil. Suitable cream media may be washable with water and include an oil phase, an emulsifier, and an aqueous phase. The oil phase is also referred to as the “inner” phase, which is generally composed of petrolatum and an aliphatic alcohol such as cetyl alcohol or stearyl alcohol. The aqueous phase is usually, but not necessarily, larger in volume than the oil phase and generally contains a humectant. The emulsifier in the cream formulation may be a nonionic, anionic, cationic or amphoteric surfactant.

  Gels are semi-solid suspension type systems. Single phase gels comprise organic polymers that are substantially uniformly dispersed throughout the liquid carrier. Suitable gelling agents include crosslinked acrylic acid polymers such as carbomers, carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; hydroxypropyl Cellulose polymers such as cellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums such as tragacanth gum and xanthan gum; sodium alginate; and gelatin include, but are not limited to. In order to prepare a uniform gel, the gelling agent can be dispersed by adding a dispersing agent such as alcohol or glycerin, or by grinding, mechanical mixing, and / or stirring.

  The pharmaceutical compositions provided herein include suppositories, pessaries, bougies, poultices or poultices, muds, powders, bandages, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons Can be administered in the form of a gel, foam, spray, or enema, rectally, urethra, vagina, or around the vagina. These dosage forms can be prepared, for example, using conventional methods such as those described in Remington's document "The Science and Practice of Pharmacy" (supra).

  Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body openings that are solid at room temperature but melt or soften at body temperature to release the active ingredient into the opening. Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories are bases, such as sclerosants, that produce a melting point near body temperature when formulated with a pharmaceutical composition provided herein or A medium; and an antioxidant as described herein comprising bisulfite and sodium metabisulfite. Suitable media are cocoa butter (cocoa butter), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white wax and yellow wax, and suitable mixtures of mono-, di- and triglycerides of fatty acids. And hydrogels such as, but not limited to, polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid and the like. Various media combinations can also be used. Rectal and vaginal suppositories can be prepared by compression or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.

  The pharmaceutical compositions provided herein are administered ophthalmically in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants. Can do.

  The pharmaceutical compositions provided herein can be administered intranasally or by inhalation into the respiratory tract. The pharmaceutical composition may be added alone or in combination with a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. It can be provided in the form of an aerosol or solution for delivery using a pressure vessel, pump, spray, atomizer such as an atomizer that uses electrohydrodynamics to generate fine mist, or a nebulizer. The pharmaceutical composition can be provided alone or in combination with an inert carrier such as lactose or phospholipids as a dry powder for insufflation; and as a nasal spray. For intranasal use, the powder may contain a bioadhesive, including chitosan or cyclodextrin.

  Solutions or suspensions for use in pressurized containers, pumps, sprays, atomizers, or nebulizers disperse, dissolve, or extend the release of ethanol, aqueous ethanol, or the active ingredient provided herein Can be formulated to include a suitable propellant; a propellant as a solvent; and / or a surfactant such as sorbitan trioleate, oleic acid, or oligolactic acid.

  The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 μm or less, or about 10 μm or less. Such sized particles may be pulverized using methods known to those skilled in the art, such as spiral jet mills, fluidized bed jet mills, supercritical fluidization to form nanoparticles, high pressure homogenization, or spray drying. Can be prepared.

  Capsules, blisters and cartridges for use in inhalers or insufflators are powder mixtures of the pharmaceutical compositions provided herein; suitable powder bases such as lactose or starch; and L-leucine, mannitol Or may be formulated to include a performance modifier, such as magnesium stearate. Lactose may be in the form of an anhydride or monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions provided herein for inhalation / intranasal administration may further comprise suitable flavors such as menthol and levomenthol; and / or sweeteners such as saccharin or saccharin sodium.

  The pharmaceutical compositions provided herein for topical administration are immediate release or modified release including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release Can be formulated.

(D. Modified release)
The pharmaceutical compositions provided herein can be formulated as a modified release dosage form. The term “modified release” as used herein refers to a dosage form in which the rate or location of release of the active ingredient is different from that of the immediate dosage form when administered by the same route. Modified release dosage forms include delayed release, extended release, extended release, sustained release, pulsed release, controlled release, accelerated release and rapid release, targeted release, and programmed release, as well as gastric retention dosage forms However, it is not limited to these. Pharmaceutical compositions that are modified release dosage forms include matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof Can be prepared using a variety of modified release devices and methods known to those skilled in the art including, but not limited to. The release rate of the active ingredient can also be modified by varying the particle size and polymorphism of the active ingredient.

Examples of modified release include, but are not limited to, those described below:

(1. Matrix controlled release device)
The pharmaceutical compositions provided herein in a modified release dosage form can be manufactured using matrix controlled release devices known to those skilled in the art (Takada et al., “Enforced controlled drug delivery”. See Cyclopedia (Encyclopedia of Controlled Drug Delivery), Volume 2, edited by Mathiowitz, Wiley, 1999).

  In some embodiments, the pharmaceutical compositions provided herein in modified release dosage forms are water swellable, including, but not limited to, synthetic polymers and natural polymers and derivatives such as polysaccharides and proteins. Formulated with an erodible matrix device, which is an erodible or soluble polymer.

  Materials useful in forming the erodible matrix include chitin, chitosan, dextran, and pullulan; agar gum, gum arabic, caraya gum, locust bean gum, tragacanth gum, carrageenan, gati gum, guar gum, xanthan gum, and scleroglucan; dextrin and malto Starch such as dextrin; hydrocolloid such as pectin; phosphatide such as lecithin; alginate; propylene glycol alginate; gelatin; collagen; ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose ( HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), C Cellulose derivatives such as AP, CAT, hydroxypropylmethylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropylmethylcellulose acetate trimellitate (HPMCAT), and ethylhydroxyethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid ester Polyacrylamide; polyacrylic acid; copolymer of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Piscataway, NJ); poly (2-hydroxyethyl-methacrylate); polylactide; L-glutamic acid and L-glutamic acid Copolymer of ethyl; degradable lactic acid-glycolic acid copolymer; poly-D-(-)-3-hydroxybutyric acid; and butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, methacrylic acid (2-dimethyla Aminoethyl), and such homopolymers and copolymers of methacrylic acid (trimethyl aminoethyl) chloride, including other acrylic acid derivatives, but are not limited thereto.

  In some embodiments, the pharmaceutical compositions provided herein are formulated with a non-erodible matrix device. The active ingredient is dissolved or dispersed in the inert matrix and is released mainly by diffusion through the inert matrix once administered. Materials suitable for use as non-erodible matrix devices are polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymer , Ethylene-vinyl acetate copolymer, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, vinyl chloride copolymer with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer , Ethylene / vinyl acetate / vinyl alcohol terpolymer, ethylene / vinyloxyethanol copolymer, polyvinyl chloride, plasticization Insoluble plastics such as Iron, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, and silicone carbonate copolymers; ethylcellulose, cellulose acetate, crospovidone, and crosslinked partially hydrolyzed Including, but not limited to, hydrophilic polymers such as polyvinyl acetate; and fatty compounds such as carnauba wax, microcrystalline wax, and triglycerides.

  In matrix controlled release systems, the desired release kinetics may be, for example, the type of polymer used, the viscosity of the polymer, the particle size of the polymer and / or active ingredient, the ratio of active ingredient to polymer, and other factors within the composition. It can be controlled via the dosage form or carrier.

  The pharmaceutical compositions provided herein in modified release dosage forms are prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt granulation followed by compression. Can be prepared.

(2. Osmotic pressure controlled release device)
The pharmaceutical compositions provided herein in modified release dosage forms include, but are not limited to, 1-chamber systems, 2-chamber systems, asymmetric membrane technology (AMT), and extruded core systems (ECS). It can be manufactured using an osmotic controlled release device that is not. In general, such devices have at least two components: (a) a core containing the active ingredient; and (b) a semipermeable membrane having at least one delivery port enclosing the core. The semipermeable membrane controls the inflow of water from the aqueous environment used to the core so that drug release is caused by extrusion through the delivery port.

  In addition to the active ingredient, the core of the osmotic device optionally includes an osmotic material that creates a driving force for the transport of water from the environment of use to the core of the device. One class of osmotic materials are water swellable hydrophilic polymers, also referred to as “osmopolymers” and “hydrogels”. Water swellable hydrophilic polymers suitable as osmotic agents include hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly (methacrylic acid 2 -Hydroxyethyl), poly (acrylic acid), poly (methacrylic acid), polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymer, methyl methacrylate and vinyl acetate and other hydrophobic monomers PVA / PVP copolymer, hydrophilic polyurethane with large PEO block, croscarmellose sodium, carrageenan, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) and carboxyethyl Ceruleau (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and including sodium starch glycolate, but is not limited thereto.

  Another osmotic class is osmogen, which is capable of absorbing and swelling water to affect the osmotic pressure gradient across the surrounding coating barrier. Suitable osmogens are inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; dextrose, fructose Sugars such as glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, Including, but not limited to, organic acids such as edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.

  Osmotic materials with different dissolution rates can be used to affect how quickly the active ingredient is initially delivered from the dosage form. Use amorphous sugars such as MANOGEMTM EZ (SPI Pharma, Lewis, DE) to provide faster delivery for the first few hours to provide the desired therapeutic action immediately, as desired The remaining amount can be released gradually and continuously in order to maintain this level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient is released at a rate that replaces the amount of active ingredient that is metabolized and excreted.

  The core may also contain a wide variety of other excipients and carriers described herein to enhance the performance of the dosage form or to promote stability or processing.

  Materials useful for the formation of semipermeable membranes are various grades of acrylic acid, vinyl, which are water permeable and water insoluble at physiologically reasonable pH, or are susceptible to water insolubility due to chemical changes such as cross-linking. Includes ethers, polyamides, polyesters, and cellulose derivatives. Examples of suitable polymers useful for forming the coating are plasticized, unplasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, cellulose acetate propionate, cellulose nitrate, butyric acetate Cellulose (CAB), cellulose acetate ethyl carbamate, CAP, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate trimellitic acid (CAT), cellulose acetate dimethylamino acetate, cellulose acetate ethyl carbonate, cellulose acetate chloroacetate, ethyl acetate Cellulose acid cellulose, cellulose acetate methyl sulfonate, cellulose acetate butyl sulfonate, cellulose acetate p-toluene sulfonate, cellulose acetate agar, amylose triacetate, β-glucan acetate, β-glucan triacetate, dimethylacetate acetaldehyde, locust bean Triacetate ester, ethylene hydroxide-vinyl acetate, EC, PEG, PPG, PEG / PPG copolymer, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly (acrylic) acid and ester and Poly (methacrylic) acid and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkene, polyether, polysulfone, polyethersulfone, polystyrene, polyvinyl halide, polyvinyl ester and ether, natural wax and synthesis Contains wax.

  The semipermeable membrane is also hydrophobic, as disclosed in US Pat. No. 5,798,119, in which the pores are substantially filled with gas and are not wetted by an aqueous medium, but are permeable to water vapor. It can also be a microporous membrane. Such hydrophobic but water vapor permeable membranes are typically polyalkene, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyether, polysulfone, polyethersulfone, polystyrene, polyvinyl halide, polyfluoride. Composed of hydrophobic polymers such as vinylidene chloride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

  Delivery ports on the semipermeable membrane can be formed after coating by mechanical or laser drilling. The delivery port can also be formed in situ by etching a plug of water soluble material or by breaking a relatively thin portion of the membrane over the core recess. In addition, delivery ports can be formed during the coating process, as in the case of asymmetric membrane coatings of the type disclosed in US Pat. Nos. 5,612,059 and 5,698,220.

  The total amount of active ingredient released and the rate of release can be substantially modified by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size and location of delivery ports.

  The pharmaceutical composition in an osmotic controlled release dosage form can further contain additional conventional excipients or carriers as described herein to facilitate formulation performance or processing.

  Osmotic controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (Remington, “The Science and Practice of Pharmacy”, supra; Sants and Baker, J. Controlled Release, 35, 1-21 (1995); Verma et al., Drug Development and Industrial Pharmacy, 26, 695-708 (2000); Verma et al., J. Controlled Release, 79, 7-27 (2002)).

  In some embodiments, a pharmaceutical composition provided herein comprises an AMT-controlled membrane comprising an asymmetric osmotic membrane covering a core containing an active ingredient and other pharmaceutically acceptable excipients or carriers. Formulated as a release form. See US Pat. No. 5,612,059 and International Publication No. WO 2002/17918. AMT controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and dip-coating methods.

  In some embodiments, the pharmaceutical compositions provided herein comprise an osmotic membrane that coats a core containing an active ingredient, hydroxylethylcellulose, and other pharmaceutically acceptable excipients or carriers. Formulated as an ESC controlled release dosage form.

(3. Multi-particle controlled release device)
The pharmaceutical compositions provided herein in a modified release dosage form have a number of particles that range in diameter from about 10 μm to about 3 mm, from about 50 μm to about 2.5 mm, or from about 100 μm to about 1 mm, It can be made as a multiparticulate controlled release device containing granules or pellets. Such multiparticulates can be made by processes known to those skilled in the art including wet-and dry-granulation, extrusion / spheronization, roller compaction, melt-solidification, and seed-core spray-coating. See, for example, “Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994;” and “Pharmaceutical Pelletization Technology”; Marcel Dekker: 1989.

  Other excipients or carriers as described herein can be formulated with the pharmaceutical composition to assist in the processing and formation of the multiparticulates. The resulting particles can themselves constitute a multiparticulate device or can be coated with various film forming materials such as enteric polymers, water swellable polymers, and water soluble polymers. The multiparticulates can be further processed as capsules or tablets.

(4. Targeted delivery)
The pharmaceutical compositions provided herein also include a specific tissue, receptor, or other of the body to be treated, including liposome-, resealed erythrocytes-, and antibody-based delivery systems. It can also be formulated to target the area. Examples include, but are not limited to, those disclosed in the following patents:

(how to use)
In one embodiment, leukemia in a subject comprising administering to the subject a therapeutically effective amount of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof. Methods of treatment are provided herein.

  In some embodiments, the leukemia is relapsed leukemia. In some embodiments, the leukemia is refractory leukemia. In some embodiments, the leukemia is drug resistant leukemia. In some embodiments, the leukemia is hereditary leukemia. In some embodiments, the hereditary leukemia is severe congenital neutropenia (SCN). In some embodiments, the hereditary leukemia is familial platelet disorder associated with acute myeloid leukemia (FDP / AML). In some embodiments, the leukemia is caused by LEF1. In some embodiments, the leukemia is mediated by LEF1. In some embodiments, the leukemia is caused by GSK3.

  In some embodiments, the leukemia is acute leukemia. In some embodiments, the leukemia is relapsed acute leukemia. In some embodiments, the leukemia is refractory acute leukemia. In some embodiments, the leukemia is drug resistant acute leukemia. In some embodiments, the leukemia is ALL. In some embodiments, the leukemia is relapsed ALL. In some embodiments, the leukemia is refractory ALL. In some embodiments, the leukemia is drug resistant ALL. In some embodiments, the leukemia is AML. In some embodiments, the leukemia is relapsed AML. In some embodiments, the leukemia is refractory AML. In some embodiments, the leukemia is drug resistant AML. In some embodiments, the AML has a RAS mutation. In some embodiments, the RAS mutation is NRAS, KRAS, or HRAS. In some embodiments, the RAS mutation is NRAS. In some embodiments, the RAS mutation is KRAS. In some embodiments, the RAS mutation is HRAS.

  In some embodiments, the leukemia is chronic leukemia. In some embodiments, the leukemia is relapsed chronic leukemia. In some embodiments, the leukemia is refractory chronic leukemia. In some embodiments, the leukemia is drug resistant chronic leukemia. In some embodiments, the leukemia is CLL. In some embodiments, the leukemia is relapsed CLL. In some embodiments, the leukemia is refractory CLL. In some embodiments, the leukemia is a drug resistant CLL. In some embodiments, the leukemia is CML. In some embodiments, the leukemia is relapsed CML. In some embodiments, the leukemia is refractory CML. In some embodiments, the leukemia is drug resistant CML. In some embodiments, the leukemia is juvenile CML. In some embodiments, the leukemia is juvenile CML with one or more NF-1 mutations.

  In some embodiments, the ALL is leukemia caused by bone marrow (B cells), thymus (T cells), or lymph node blasts. ALL follows the French-US-British (FAB) morphological classification scheme, L1-maturated lymphoblasts (T cells or progenitor B cells), L2- immature and polymorphic (various forms of ) Lymphoblasts (T cells or progenitor B cells), and L3-lymphoblasts (B cells; Burkitt cells). In one embodiment, ALL originates from bone marrow (B cell) blasts. In another embodiment, ALL originates from the thymus (T cell). In yet another embodiment, ALL originates from a lymph node. In yet another embodiment, ALL is the L1 type characterized by lymphoblasts (T cells or progenitor B cells) that appear in the mature form. In yet another embodiment, ALL is of the L2 type characterized by immature and polymorphic (various forms) lymphoblasts (T cells or progenitor B cells). In yet another embodiment, ALL is type L3 characterized by lymphoblasts (B cells; Burkitt cells).

  In some embodiments, the AML is undifferentiated AML (MO), myeloblastic leukemia (M1), myeloblastic leukemia (M2), promyelocytic leukemia (M3 or M3 variant [M3V]) Myelomonocytic leukemia (M4 variant with M4 or eosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia (M6), or megakaryoblastic leukemia (M7). In one embodiment, the AML is undifferentiated AML (MO). In another embodiment, the AML is myeloblastic leukemia (M1). In yet another embodiment, the AML is myeloblastic leukemia (M2). In yet another embodiment, the AML is promyelocytic leukemia (M3 or M3 variant [M3V]). In yet another embodiment, the AML is myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]). In yet another embodiment, the AML is monocytic leukemia (M5). In yet another embodiment, the AML is erythroleukemia (M6). In yet another embodiment, the AML is megakaryoblastic leukemia (M7).

  In some embodiments, the leukemia is T cell leukemia. In one embodiment, the T cell leukemia is peripheral T cell leukemia, T cell lymphoblastic leukemia, cutaneous T cell leukemia, and adult T cell leukemia. In another embodiment, the T cell leukemia is peripheral T cell leukemia. In yet another embodiment, the T cell leukemia is T cell lymphoblastic leukemia. In yet another embodiment, the T cell leukemia is cutaneous T cell leukemia. In yet another embodiment, the T cell leukemia is adult T cell leukemia.

  In some embodiments, the leukemia is Philadelphia positive. In one embodiment, the leukemia is undifferentiated AML (M0), myeloblastic leukemia (M1), myeloblastic leukemia (M2), promyelocytic leukemia (M3 or M3 variant [M3V]), bone marrow Monocytic leukemia (M4 or M4 variant with eosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia (M6), or megakaryoblastic leukemia (M7) Without limitation, Philadelphia positive AML. In another embodiment, the leukemia is Philadelphia positive ALL. In yet another embodiment, the leukemia is Philadelphia positive CLL. In yet another embodiment, the leukemia is Philadelphia positive CML.

  In another embodiment, in a subject comprising administering to the subject a therapeutically effective amount of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof. Provided herein are methods for treating CLL.

  In yet another embodiment, the subject comprising administering to the subject a therapeutically effective amount of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof. Methods of treating drug resistant hematologic malignancies in are provided herein.

In some embodiments, the drug resistant hematologic malignancy is a relapsed drug resistant hematologic malignancy. In some embodiments, the drug resistant hematologic malignancy is an intractable drug resistant hematologic malignancy. In some embodiments, the drug resistant hematologic malignancy is a multidrug resistant hematologic malignancy. In some embodiments, the drug resistant hematologic malignancy is a Bcr-Abl kinase inhibitor resistant hematologic malignancy. In some embodiments, the drug resistant hematologic malignancy is imatinib-resistant hematologic malignancy. In some embodiments, the drug resistant hematologic malignancy is dasatinib-resistant hematologic malignancy. In some embodiments, the drug resistant hematologic malignancy is nilotinib -resistant hematologic malignancy. In some embodiments, the drug resistant hematologic malignancy is bosutinib-resistant hematologic malignancy. In some embodiments, the drug resistant hematologic malignancy is cytarabine-resistant hematologic malignancy. In some embodiments, the drug resistant hematologic malignancy is a vincristine-resistant hematologic malignancy.

  In some embodiments, the drug resistant hematologic malignancy is a drug resistant myeloma, leukemia, myeloproliferative disorder, acute myeloid leukemia (AML) (FLT3-mediated and / or KIT-mediated and / or CSFlR-mediated acute myeloid leukemia), chronic myelogenous leukemia (CML) (including FLT3-mediated and / or PDGFR-mediated chronic myelogenous leukemia), myelodysplastic leukemia (including FLT3-mediated myeloid leukemia) Myelodysplastic syndrome (including FLT3-mediated and / or Kit-mediated myelodysplastic syndrome), idiopathic eosinophilia syndrome (HES) (including PDGFR-mediated HES), chronic Eosinophilic leukemia (CEL) (including PDGFR-mediated CEL), chronic myelomonocytic leukemia (CMML), mast cell leukemia (including Kit-mediated mast cell leukemia), or systemic mastocytosis ( Kit-mediated systemic mastocytosis).

  In some embodiments, the drug resistant hematologic malignancy is a drug resistant lymphoma, lymphoproliferative disease, acute lymphoblastic leukemia (ALL), B cell acute lymphoblastic leukemia, T cell acute lymphoblast Spherical leukemia, chronic lymphocytic leukemia (CLL), natural killer (NK) cell leukemia, B cell lymphoma, T cell lymphoma, or natural killer (NK) cell lymphoma.

  In some embodiments, the drug resistant hematologic malignancy is a drug resistant Langerhans cell histiocytosis (including CSF-1R-mediated and / or FLT3-mediated Langerhans cell histiocytosis), obesity Cell tumor or mastocytosis.

In some embodiments, the drug resistant hematologic malignancy is drug resistant leukemia. In some embodiments, the drug resistant leukemia is relapsed drug resistant leukemia. In some embodiments, the drug resistant leukemia is refractory drug resistant leukemia. In some embodiments, the drug resistant leukemia is multidrug resistant leukemia. In some embodiments, the drug resistant leukemia is a Bcr-Abl kinase inhibitor resistant leukemia. In some embodiments, the drug resistant leukemia is imatinib-resistant leukemia. In some embodiments, the drug resistant leukemia is dasatinib-resistant leukemia. In some embodiments, the drug resistant leukemia is nilotinib -resistant leukemia. In some embodiments, the drug resistant leukemia is bostinib-resistant leukemia. In some embodiments, the drug resistant leukemia is cytarabine-resistant leukemia. In some embodiments, the drug resistant leukemia is vincristine-resistant leukemia.

In some embodiments, the drug resistant leukemia is a drug resistant acute leukemia. In some embodiments, the drug resistant leukemia is relapsed drug resistant acute leukemia. In some embodiments, the drug resistant leukemia is refractory drug resistant acute leukemia. In some embodiments, the drug resistant leukemia is multidrug resistant acute leukemia. In some embodiments, the drug resistant leukemia is Bcr-Abl kinase inhibitor resistant acute leukemia. In some embodiments, the drug resistant leukemia is imatinib-resistant acute leukemia. In some embodiments, the drug resistant leukemia is dasatinib-resistant acute leukemia. In some embodiments, the drug resistant leukemia is nilotinib -resistant acute leukemia. In some embodiments, the drug resistant leukemia is bosutinib-resistant acute leukemia. In some embodiments, the drug resistant leukemia is cytarabine-resistant acute leukemia. In some embodiments, the drug resistant leukemia is vincristine-resistant acute leukemia.

In some embodiments, the drug resistant leukemia is multidrug resistant ALL. In some embodiments, the drug resistant leukemia is Bcr-Abl kinase inhibitor resistant ALL. In some embodiments, the drug resistant leukemia is imatinib-resistant ALL. In some embodiments, the drug resistant leukemia is dasatinib-resistant ALL. In some embodiments, the drug resistant leukemia is nilotinib -resistant ALL. In some embodiments, the drug resistant leukemia is bosutinib-resistant ALL. In some embodiments, the drug resistant leukemia is cytarabine-resistant ALL. In some embodiments, the drug resistant leukemia is vincristine-resistant ALL.

In some embodiments, the drug resistant leukemia is multidrug resistant AML. In some embodiments, the drug resistant leukemia is Bcr-Abl kinase inhibitor resistant AML. In some embodiments, the drug resistant leukemia is imatinib-resistant AML. In some embodiments, the drug resistant leukemia is dasatinib-resistant AML. In some embodiments, the drug resistant leukemia is nilotinib -resistant AML. In some embodiments, the drug resistant leukemia is bosutinib-resistant AML. In some embodiments, the drug resistant leukemia is cytarabine-resistant AML. In some embodiments, the drug resistant leukemia is vincristine-resistant AML.

In some embodiments, the drug resistant leukemia is a drug resistant chronic leukemia. In some embodiments, the drug resistant leukemia is relapsed drug resistant chronic leukemia. In some embodiments, the drug resistant leukemia is refractory drug resistant chronic leukemia. In some embodiments, the drug resistant leukemia is multidrug resistant chronic leukemia. In some embodiments, the drug resistant leukemia is Bcr-Abl kinase inhibitor resistant chronic leukemia. In some embodiments, the drug resistant leukemia is imatinib-resistant chronic leukemia. In some embodiments, the drug resistant leukemia is dasatinib-resistant chronic leukemia. In some embodiments, the drug resistant leukemia is nilotinib -resistant chronic leukemia. In some embodiments, the drug resistant leukemia is bosutinib-resistant chronic leukemia. In some embodiments, the drug resistant leukemia is cytarabine-resistant chronic leukemia. In some embodiments, the drug resistant leukemia is vincristine-resistant chronic leukemia.

In some embodiments, the drug resistant leukemia is a multidrug resistant CLL. In some embodiments, the drug resistant leukemia is Bcr-Abl kinase inhibitor resistant CLL. In some embodiments, the drug resistant leukemia is imatinib-resistant CLL. In some embodiments, the drug resistant leukemia is dasatinib-resistant CLL. In some embodiments, the drug resistant leukemia is nilotinib -resistant CLL. In some embodiments, the drug resistant leukemia is bosutinib-resistant CLL. In some embodiments, the drug resistant leukemia is cytarabine-resistant CLL. In some embodiments, the drug resistant leukemia is vincristine-resistant CLL.

In some embodiments, the drug resistant leukemia is multidrug resistant CML. In some embodiments, the drug resistant leukemia is Bcr-Abl kinase inhibitor resistant CML. In some embodiments, the drug resistant leukemia is imatinib-resistant CML. In some embodiments, the drug resistant leukemia is dasatinib-resistant CML. In some embodiments, the drug resistant leukemia is nilotinib -resistant CML. In some embodiments, the drug resistant leukemia is bosutinib-resistant CML. In some embodiments, the drug resistant leukemia is cytarabine-resistant CML. In some embodiments, the drug resistant leukemia is vincristine-resistant CML.

  In some embodiments, the drug resistant leukemia is Philadelphia positive. In one embodiment, the drug resistant leukemia is undifferentiated AML (M0), myeloblastic leukemia (M1), myeloblastic leukemia (M2), promyelocytic leukemia (M3 or M3 variant [M3V] ), Myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia (M6), or megakaryoblastic leukemia (M7) Without limitation, Philadelphia positive AML. In another embodiment, the drug resistant leukemia is Philadelphia positive ALL. In yet another embodiment, the drug resistant leukemia is Philadelphia positive CLL. In yet another embodiment, the drug resistant leukemia is Philadelphia positive CML.

In yet another embodiment, the subject comprising administering to the subject a therapeutically effective amount of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof. Methods of treating drug resistant leukemia in are provided herein. In one embodiment, the leukemia is resistant to a Bcr-Abl kinase inhibitor. In another embodiment, the leukemia is resistant to imatinib, dasatinib, nilotinib , bosutinib, cytarabine, or vincristine. In yet another embodiment, the leukemia is resistant to dasatinib, nilotinib , bosutinib, cytarabine, or vincristine.

In yet another embodiment, the subject comprising administering to the subject a therapeutically effective amount of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof. Methods for the treatment of drug resistant acute leukemia in are provided herein. In one embodiment, the acute leukemia is resistant to a Bcr-Abl kinase inhibitor. In another embodiment, the acute leukemia is resistant to imatinib, dasatinib, nilotinib , bosutinib, cytarabine, or vincristine. In yet another embodiment, the acute leukemia is resistant to dasatinib, nilotinib , bosutinib, cytarabine, or vincristine.

In yet another embodiment, the subject comprising administering to the subject a therapeutically effective amount of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof. Provided herein are methods for treating drug resistant ALL in In one embodiment, ALL is resistant to a Bcr-Abl kinase inhibitor. In another embodiment, ALL is resistant to imatinib, dasatinib, nilotinib , bosutinib, cytarabine, or vincristine. In yet another embodiment, ALL is resistant to dasatinib, nilotinib , bosutinib, cytarabine, or vincristine.

In yet another embodiment, the subject comprising administering to the subject a therapeutically effective amount of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof. Methods of treating drug resistant AML in are provided herein. In one embodiment, the AML is resistant to Bcr-Abl kinase inhibitors. In another embodiment, the AML is resistant to imatinib, dasatinib, nilotinib , bosutinib, cytarabine, or vincristine. In yet another embodiment, the AML is resistant to dasatinib, nilotinib , bosutinib, cytarabine, vincristine.

In yet another embodiment, the subject comprising administering to the subject a therapeutically effective amount of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof. Methods of treating drug resistant chronic leukemia in are provided herein. In one embodiment, the chronic leukemia is resistant to a Bcr-Abl kinase inhibitor. In another embodiment, the chronic leukemia is resistant to imatinib, dasatinib, nilotinib , bosutinib, cytarabine, or vincristine. In yet another embodiment, the chronic leukemia is resistant to dasatinib, nilotinib , bosutinib, cytarabine, or vincristine.

In yet another embodiment, the subject comprising administering to the subject a therapeutically effective amount of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof. Methods of treating drug resistant CLL in are provided herein. In one embodiment, the CLL is resistant to a Bcr-Abl kinase inhibitor. In another embodiment, the CLL is resistant to imatinib, dasatinib, nilotinib , bosutinib, cytarabine, or vincristine. In yet another embodiment, the CLL is resistant to dasatinib, nilotinib , bosutinib, cytarabine, or vincristine.

In yet another embodiment, the subject comprising administering to the subject a therapeutically effective amount of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof. Methods of treating drug resistant CML in are provided herein. In one embodiment, CML is resistant to a Bcr-Abl kinase inhibitor. In another embodiment, the CML is resistant to imatinib, dasatinib, nilotinib , bosutinib, cytarabine, or vincristine. In yet another embodiment, the CML is resistant to dasatinib, nilotinib , bosutinib, cytarabine, or vincristine.

  In some embodiments, the therapeutically effective amount is about 0.1 to about 100 mg / kg / day, about 0.1 to about 50 mg / kg / day, about 0.1 to about 40 mg / kg / day, about 0.1 to about 30 mg / kg. / Day, about 0.1 to about 25 mg / kg / day, about 0.1 to about 20 mg / kg / day, about 0.1 to about 15 mg / kg / day, about 0.1 to about 10 mg / kg / day, or about 0.1 to about 5 mg / day The range is kg / day. In one embodiment, the therapeutically effective amount ranges from about 0.1 to about 100 mg / kg / day. In another embodiment, the therapeutically effective amount ranges from about 0.1 to about 50 mg / kg / day. In yet another embodiment, the therapeutically effective amount ranges from about 0.1 to about 40 mg / kg / day. In yet another embodiment, the therapeutically effective amount ranges from about 0.1 to about 30 mg / kg / day. In yet another embodiment, the therapeutically effective amount ranges from about 0.1 to about 25 mg / kg / day. In yet another embodiment, the therapeutically effective amount ranges from about 0.1 to about 20 mg / kg / day. In yet another embodiment, the therapeutically effective amount ranges from about 0.1 to about 15 mg / kg / day. In yet another embodiment, the therapeutically effective amount ranges from about 0.1 to about 10 mg / kg / day. In yet another embodiment, the therapeutically effective amount ranges from about 0.1 to about 5 mg / kg / day.

  In some embodiments, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is administered orally. In some embodiments, the therapeutically effective amount for oral administration ranges from about 0.1 to about 100, from about 0.5 to about 50, or from about 1 to about 25 mg / kg / day. In some embodiments, the therapeutically effective amount for oral administration is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, About 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28 , About 29, or about 30 mg / kg / day. In some embodiments, the therapeutically effective amount for oral administration is about 2, about 5, about 10, about 15, or about 20 mg / kg / day. In some embodiments, the therapeutically effective amount for oral administration is about 1 mg / kg / day. In some embodiments, the therapeutically effective amount for oral administration is about 2 mg / kg / day. In some embodiments, the therapeutically effective amount for oral administration is about 5 mg / kg / day. In some embodiments, the therapeutically effective amount for oral administration is about 10 mg / kg / day. In some embodiments, the therapeutically effective amount for oral administration is about 15 mg / kg / day. In some embodiments, the therapeutically effective amount for oral administration is about 20 mg / kg / day.

  In some embodiments, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is administered intravenously. In some embodiments, the therapeutically effective amount for oral administration is about 0.001 to about 20, about 0.01 to about 10, about 0.01 to about 5, about 0.05 to about 1 mg / kg / day, about 0.05 to about 0.95. Or about 0.05 to about 0.90 mg / kg / day. In some embodiments, the therapeutically effective amount for intravenous administration is about 0.05, about 0.06, about 0.08, about 0.1, about 0.15, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7. About 0.8, about 0.9, about 0.95, about 0.99, or about 1 mg / kg / day. In some embodiments, the therapeutically effective amount for intravenous administration is about 0.1 mg / kg / day. In some embodiments, the therapeutically effective amount for intravenous administration is about 0.2 mg / kg / day. In some embodiments, the therapeutically effective amount for intravenous administration is about 0.3 mg / kg / day. In some embodiments, the therapeutically effective amount for intravenous administration is about 0.5 mg / kg / day.

It will be appreciated that the dose administered can be expressed in units other than mg / kg / day. For example, the dosage for parenteral administration can be expressed as mg / m ² / day. One skilled in the art will readily know how to convert doses from mg / kg / day to mg / m ² / day for a given subject's height or weight or both (www.fda .gov / cder / cancer / animalframe.htm). For example, a dose of 1 mg / m ² / day for 65 kg human is approximately equal to 38 mg / kg / day.

  In yet another embodiment, ciclopirox or a therapeutically acceptable salt or solvate thereof is about 0.01 to about 100 μM, about 0.1 to about 50 μM, about 0.2 to about 20 μM, about 1 to about 20 μM at steady state, or Provided herein is a method of treating leukemia or drug-resistant hematologic malignancy in a subject comprising administering to the subject an amount sufficient to provide a ciclopirox plasma concentration that ranges from about 5 to about 20 μM. . In one embodiment, the amount of ciclopirox administered is sufficient to provide a ciclopirox plasma concentration that ranges from about 1 to about 20 μM at steady state. In another embodiment, the amount of ciclopirox administered is sufficient to provide a ciclopirox plasma concentration that is about 1, about 2, about 5, about 10, or about 20 μM at steady state. As used herein, the term “steady state plasma concentration” is the concentration reached after a period of administration of a compound. Once steady state is reached, there are small peaks and troughs on the curve corresponding to the time of plasma concentration of the compound.

  In yet another embodiment, ciclopirox or a therapeutically acceptable salt or solvate thereof is about 0.01 to about 100 μM, about 0.1 to about 50 μM, about 0.2 to about 20 μM, about 1 to about 20 μM, or about 5 to A method of treating leukemia or drug-resistant hematologic malignancy in a subject, comprising administering to the subject an amount sufficient to provide a maximum ciclopirox plasma concentration (peak concentration) that is in the range of about 20 μM. provide. In one embodiment, the amount of ciclopirox administered is sufficient to provide a maximum plasma concentration that ranges from about 1 to about 50 μM. In another embodiment, the amount of ciclopirox administered provides a maximum plasma concentration of about 1, about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 40, or about 50 μM. Enough to do.

  In yet another embodiment, ciclopirox or a therapeutically acceptable salt or solvate thereof is administered in two or more doses of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone. To provide a maximum plasma concentration (peak concentration) of ciclopirox that is in the range of about 0.01 to about 100 μM, about 0.1 to about 50 μM, about 0.2 to about 20 μM, about 1 to about 20 μM, or about 5 to about 20 μM. Provided herein is a method of treating leukemia or drug resistant hematologic malignancy in a subject comprising administering to a subject in a sufficient amount. In one embodiment, the amount of ciclopirox administered is from about 1 to about 50 μM when two or more doses of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone are administered. It is sufficient to provide the highest plasma concentration that is in the range. In another embodiment, the amount of ciclopirox administered is about 1, about 2 when two or more doses of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone are administered. Sufficient to provide a maximum plasma concentration of about 5, about 10, about 15, about 20, about 25, about 30, about 40, or about 50 μM.

In yet another embodiment, the ciclopirox has a half-life (t of about 1 to about 200 hours, about 2 to about 100 hours, about 5 to about 50 hours, about 5 to 25 hours, or about 5 to 10 hours. having _1/2), the ciclopirox or how a salt or solvate acceptable as a treatment comprising administering to the subject a, to treat leukemia or drug-resistant hematologic malignancies in a subject, provided herein To do. In one embodiment, the ciclopirox has a half-life (t _1/2 ) of about 5, about 7, about 10, about 15, about 20, about 40, about 60, about 80, or about 100 hours.

  In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

  In some embodiments, the subject treated by one of the methods provided herein is a leukemia or drug to be treated prior to administration of ciclopirox or a pharmaceutically acceptable salt or solvate thereof. Not treated with anticancer therapy for resistant hematologic malignancies.

  In some embodiments, the subject treated by one of the methods provided herein is a leukemia or drug to be treated prior to administration of ciclopirox or a pharmaceutically acceptable salt or solvate thereof. It is treated with anticancer therapy for resistant hematological malignancies.

  In some embodiments, the subject treated by one of the methods provided herein has an age of about 1 to about 100 years, about 1 to about 10 years, about 1 to about 15 years, about 1 Range from about 20 years old, about 10 to about 20 years old, about 15 to about 85 years old, about 40 to about 85 years old, or about 55 to about 85 years old.

  The methods provided herein include treating a subject regardless of the age of the patient, even though some diseases or disorders are more common in certain age groups. Further provided herein are methods for treating subjects who have not undergone surgery in addition to subjects who have undergone surgery in an attempt to treat the disease or condition in question. Because subjects with cancer have non-uniform clinical manifestations and varying clinical outcomes, the treatment given to a particular subject can vary depending on the prognosis of that subject. Skilled clinicians are not based on specific secondary drugs, surgical types, and drugs that can be used effectively to treat individual subjects with cancer without undue experimentation The type of standard therapy will be readily determinable.

  Depending on the disease to be treated and the condition of the subject, ciclopirox or a pharmaceutically acceptable salt or solvate may be administered orally, parenterally (e.g. intramuscular, intraperitoneal, intravenous, CIV, intracapsular injection or infusion. , Subcutaneous injection, or implantation), inhalation, nasal, vaginal, rectal, sublingual, or topical (eg, transdermal or local) routes of administration.

  Ciclopirox or a pharmaceutically acceptable salt or solvate thereof is preferably formulated for each route of administration, alone or in a suitable dose with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles. Can do.

  In one embodiment, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is administered orally. In another embodiment, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is administered parenterally. In yet another embodiment, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is administered intravenously. In yet another embodiment, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is administered intramuscularly. In yet another embodiment, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is administered subcutaneously. In yet another embodiment, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is administered topically.

  In some embodiments, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is delivered as a single bolus injection in one embodiment, a single dose such as an oral tablet or pill in another embodiment. The In some embodiments, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is a time such as continuous infusion over time in one embodiment, divided bolus dose over time in another embodiment, etc. To be delivered.

  Ciclopirox or a pharmaceutically acceptable salt or solvate thereof is administered repeatedly as necessary, for example, until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. can do. For example, a stable disease of solid cancer generally means that the measurable vertical diameter of the lesion does not increase by more than 25% from the final measurement result. Guidelines for the determination of therapeutic effects on solid cancer (RECIST) (Journal of the National Cancer Institute 92 (3): 205-216 (2000). Stable disease or lack thereof is assessed by patient symptoms, physical examination, X -Determined by methods known in the art such as visualization of tumors imaged using line, CAT, PET, or MRI scans, and other commonly accepted evaluation modalities.

  Ciclopirox or a pharmaceutically acceptable salt or solvate thereof is administered once daily (QD) or in divided daily doses such as twice daily (BID) and three times daily (TID). can do. In addition, administration can be continuous, ie daily, or intermittent. As used herein, the term “intermittent” or “intermittently” is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of ciclopirox or a pharmaceutically acceptable salt or solvate thereof can be administered for 1 to 6 days per week, cycled administration (e.g., administered daily for 2 to 8 consecutive weeks, followed by up to 1 week thereafter). (Drug holiday without administration) or every other day. In some embodiments, ciclopirox or 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof, or a pharmaceutically acceptable salt or solvent thereof The Japanese product is administered once a day, twice a day, or three times a day for about 1 to about 26 times for 6 weeks.

  In some embodiments, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is cycled to a patient. Cycle therapy involves the administration of a period of ciclopirox or a pharmaceutically acceptable salt or solvate thereof, followed by a period of withdrawal, and the repetition of this sequential administration. Cycle therapy can reduce the occurrence of resistance to one or more therapies, avoid or reduce one side effect of the therapy, and / or improve the effectiveness of the treatment.

  In some embodiments, the frequency of administration of ciclopirox or a pharmaceutically acceptable salt or solvate thereof ranges from about a daily dose to about a monthly dose. In some embodiments, administration is once a day, twice a day, three times a day, four times a day, every other day, twice a week, once a week, once every two weeks, Once every 3 weeks or once every 4 weeks. In one embodiment, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is administered once daily. In another embodiment, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is administered twice daily. In yet another embodiment, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is administered three times daily. In yet another embodiment, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is administered four times a day.

  In some embodiments, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is from 1 day to 6 months, from 1 week to 3 months, from 1 week to 4 weeks, from 1 week to 3 weeks, Or once a day for 1 to 2 weeks. In some embodiments, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is about 1 week, 2 weeks, 3 weeks, about 4 weeks, about 6 weeks, about 9 weeks, about 12 weeks, about 15 weeks. It is administered once a day for a week, about 18 weeks, about 21 weeks, or about 26 weeks.

  In some embodiments, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is administered intermittently. In some embodiments, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is administered continuously. In some embodiments, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is cycled to a patient.

  In some embodiments, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks, 15 weeks, or It is administered daily in single or divided doses for 20 weeks, followed by a drug holiday of about 1 day to about 10 weeks. For example, the method is intended to use cycles of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks, 15 weeks, or 20 weeks. In some embodiments, ciclopirox or a pharmaceutically acceptable salt or solvate thereof is 1, 3, 5, 7, 9, 12, 14, 16, 18, 20, 22, 24, 26, 28, Administered daily in single or divided doses for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks, with a 29 or 30 day drug holiday. In some embodiments, the drug holiday is 14 days. In some embodiments, the drug holiday is 28 days. In one embodiment, the drug holiday is a period sufficient for bone marrow recovery. The frequency, number and length of dosing cycles can be increased or decreased.

  In some embodiments, the methods provided herein include: i) administering to a subject an initial daily dose of ciclopirox or a pharmaceutically acceptable salt or solvate thereof; ii) at least one day During the drug holiday, no ciclopirox or a pharmaceutically acceptable salt or solvate thereof is administered to the subject during this period; iii) administering a second dose of ciclopirox or a pharmaceutically acceptable salt or solvate thereof to the subject And iv) repeating steps ii) to iii) multiple times.

  Ciclopirox or a pharmaceutically acceptable salt or solvate thereof can also be provided as a product using packaging materials well known to those skilled in the art. See, for example, US Pat. Nos. 5,323,907; 5,052,558; and 5,033,252. Examples of pharmaceutical packaging materials include blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes and any packaging material suitable for the selected formulation and intended mode of administration and treatment. Including, but not limited to.

  In some embodiments, also provided herein are kits that can facilitate the administration of an appropriate amount of an active ingredient to a subject when used by a healthcare professional. In some embodiments, the kits provided herein comprise a container and a dosage form of ciclopirox or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the kit comprises a container containing a dosage form of ciclopirox or a pharmaceutically acceptable salt or solvate thereof.

  The kits provided herein further include a device used to administer the active ingredient. Examples of such devices include, but are not limited to, syringes, needleless injectors, drip bags, patches, and inhalers. The kit provided herein can also include a condom for administration of the active ingredient.

  The kits provided herein can further comprise a pharmaceutically acceptable vehicle that can be used to administer one or more active ingredients. For example, if the active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit will dissolve the active ingredient so that a sterile solution free of particles suitable for parenteral administration is formed. A closed container of a suitable medium that can be included can be included. Examples of pharmaceutically acceptable vehicles include water for injection (US Pharmacopeia), sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, lactated Ringer's injection, etc. A water-miscible medium such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, Non-aqueous media include, but are not limited to, isopropyl myristate, benzyl benzoate, and the like.

  In some embodiments, provided herein is a method of inhibiting leukemia stem cell growth comprising contacting ciclopirox or a pharmaceutically acceptable salt or solvate thereof with a leukemia stem cell. In some embodiments, an effective amount of ciclopirox ranges from about 1 pM to about 1 mM, from about 10 pM to about 10 μM, from about 100 pM to about 2 μM, or from about 1 nM to about 1 μM.

In some embodiments, the leukemia stem cell is a relapsed leukemia stem cell. In some embodiments, the leukemia stem cell is a refractory leukemia stem cell. In some embodiments, the leukemia stem cell is a drug resistant leukemia stem cell. In some embodiments, the leukemia stem cell is a multidrug resistant leukemia stem cell. In some embodiments, the leukemia stem cell is a Bcr-Abl kinase inhibitor resistant leukemia stem cell. In some embodiments, the leukemia stem cell is an imatinib-resistant leukemia stem cell. In some embodiments, the leukemia stem cell is a dasatinib-resistant leukemia stem cell. In some embodiments, the leukemia stem cell is a nilotinib -resistant leukemia stem cell. In some embodiments, the leukemia stem cell is a bosutinib-resistant leukemia stem cell. In some embodiments, the leukemia stem cell is a cytarabine-resistant leukemia stem cell. In some embodiments, the leukemia stem cell is a vincristine-resistant leukemia stem cell.

In some embodiments, the leukemia stem cell is an acute leukemia stem cell. In some embodiments, the leukemia stem cell is a relapsed acute leukemia stem cell. In some embodiments, the leukemia stem cell is a refractory acute leukemia stem cell. In some embodiments, the leukemia stem cell is a drug resistant acute leukemia stem cell. In some embodiments, the leukemia stem cell is a multidrug resistant acute leukemia stem cell. In some embodiments, the leukemia stem cell is a Bcr-Abl kinase inhibitor resistant acute leukemia stem cell. In some embodiments, the leukemia stem cell is an imatinib-resistant acute leukemia stem cell. In some embodiments, the leukemia stem cell is a dasatinib-resistant acute leukemia stem cell. In some embodiments, the leukemia stem cell is a nilotinib -resistant acute leukemia stem cell. In some embodiments, the leukemia stem cell is a bosutinib-resistant acute leukemia stem cell. In some embodiments, the leukemia stem cell is a cytarabine-resistant acute leukemia stem cell. In some embodiments, the leukemia stem cell is a vincristine-resistant acute leukemia stem cell.

In some embodiments, the leukemia stem cell is an ALL stem cell. In some embodiments, the leukemia stem cell is a relapsed ALL stem cell. In some embodiments, the leukemia stem cell is a refractory ALL stem cell. In some embodiments, the leukemia stem cell is a drug resistant ALL stem cell. In some embodiments, the leukemia stem cell is a multidrug resistant ALL stem cell. In some embodiments, the leukemia stem cell is a Bcr-Abl kinase inhibitor resistant ALL stem cell. In some embodiments, the leukemia stem cell is an imatinib-resistant ALL stem cell. In some embodiments, the leukemia stem cell is a dasatinib-resistant ALL stem cell. In some embodiments, the leukemia stem cell is a nilotinib -resistant ALL stem cell. In some embodiments, the leukemia stem cell is a bosutinib-resistant ALL stem cell. In some embodiments, the leukemia stem cell is a cytarabine-resistant ALL stem cell. In some embodiments, the leukemia stem cell is a vincristine-resistant ALL stem cell.

In some embodiments, the leukemia stem cell is an AML stem cell. In some embodiments, the leukemia stem cell is a relapsed AML stem cell. In some embodiments, the leukemia stem cell is a refractory AML stem cell. In some embodiments, the leukemia stem cell is a drug resistant AML stem cell. In some embodiments, the leukemia stem cell is a multidrug resistant AML stem cell. In some embodiments, the leukemia stem cell is a Bcr-Abl kinase inhibitor resistant AML stem cell. In some embodiments, the leukemia stem cell is an imatinib-resistant AML stem cell. In some embodiments, the leukemia stem cell is a dasatinib-resistant AML stem cell. In some embodiments, the leukemia stem cell is a nilotinib -resistant AML stem cell. In some embodiments, the leukemia stem cell is a bosutinib-resistant AML stem cell. In some embodiments, the leukemia stem cell is a cytarabine-resistant AML stem cell. In some embodiments, the leukemia stem cell is a vincristine-resistant AML stem cell.

In some embodiments, the leukemia stem cell is a chronic leukemia cell. In some embodiments, the leukemia stem cell is a relapsed chronic leukemia cell. In some embodiments, the leukemic stem cells are refractory chronic leukemia cells. In some embodiments, the leukemia stem cell is a drug resistant chronic leukemia cell. In some embodiments, the leukemia stem cell is a multidrug resistant chronic leukemia cell. In some embodiments, the leukemia stem cell is a Bcr-Abl kinase inhibitor resistant chronic leukemia cell. In some embodiments, the leukemic stem cell is an imatinib-resistant chronic leukemia cell. In some embodiments, the leukemia stem cell is a dasatinib-resistant chronic leukemia cell. In some embodiments, the leukemia stem cell is a nilotinib -resistant chronic leukemia cell. In some embodiments, the leukemia stem cell is a bosutinib-resistant chronic leukemia cell. In some embodiments, the leukemia stem cell is a cytarabine-resistant chronic leukemia cell. In some embodiments, the leukemia stem cell is a vincristine-resistant chronic leukemia cell.

In some embodiments, the leukemia stem cell is a CLL stem cell. In some embodiments, the leukemia stem cell is a relapsed CLL stem cell. In some embodiments, the leukemia stem cell is a refractory CLL stem cell. In some embodiments, the leukemia stem cell is a drug resistant CLL stem cell. In some embodiments, the leukemia stem cell is a multidrug resistant CLL stem cell. In some embodiments, the leukemia stem cell is a Bcr-Abl kinase inhibitor resistant CLL stem cell. In some embodiments, the leukemia stem cell is an imatinib-resistant CLL stem cell. In some embodiments, the leukemia stem cell is a dasatinib-resistant CLL stem cell. In some embodiments, the leukemia stem cell is a nilotinib -resistant CLL stem cell. In some embodiments, the leukemia stem cell is a bosutinib-resistant CLL stem cell. In some embodiments, the leukemia stem cell is a cytarabine-resistant CLL stem cell. In some embodiments, the leukemia stem cell is a vincristine-resistant CLL stem cell.

In some embodiments, the leukemia stem cell is a CML stem cell. In some embodiments, the leukemia stem cell is a relapsed CML stem cell. In some embodiments, the leukemia stem cell is a refractory CML stem cell. In some embodiments, the leukemia stem cell is a drug resistant CML stem cell. In some embodiments, the leukemia stem cell is a multidrug resistant CML stem cell. In some embodiments, the leukemia stem cell is a Bcr-Abl kinase inhibitor resistant CML stem cell. In some embodiments, the leukemia stem cell is an imatinib-resistant CML stem cell. In some embodiments, the leukemia stem cell is a dasatinib-resistant CML stem cell. In some embodiments, the leukemia stem cell is a nilotinib -resistant CML stem cell. In some embodiments, the leukemia stem cell is a bosutinib-resistant CML stem cell. In some embodiments, the leukemia stem cell is a cytarabine-resistant CML stem cell. In some embodiments, the leukemia stem cell is a vincristine-resistant CML stem cell.

  In some embodiments, the leukemia stem cell is a Philadelphia positive leukemia stem cell. In one embodiment, the leukemia stem cell is a Philadelphia positive ALL stem cell. In another embodiment, the leukemia stem cell is a Philadelphia positive AML stem cell. In yet another embodiment, the leukemia stem cell is a Philadelphia positive CLL stem cell. In yet another embodiment, the leukemia stem cell is a Philadelphia positive CML stem cell.

Inhibition of cell growth is assessed by counting the number of cells contacted with the compound of interest, comparing cell growth to otherwise identical cells not contacted with the compound, or measuring the size of the tumor containing the cells can do. In addition to the number of cells, the size of the cells using any method known in the art (e.g., trypan blue size exclusion and cell counting, ³ H- measurement of thymidine incorporation into nascent DNA in a cell) Can be easily evaluated.

  The present disclosure will be further understood by the following non-limiting examples.

(Example)
The symbols and conventions used in these processes, schemes and examples used herein, for example, regardless of whether a specific abbreviation is specifically defined, for example, Journal of the American Chemical Society or Journal of It is consistent with that used in modern scientific literature such as Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout this specification: g (grams); mg (milligrams); mL (milliliters); μL (microliters) MM (mmol); μM (micromolar); Hz (hertz); MHz (megahertz); mmol (mmol); hr or hrs (hours); min (minutes); and DMSO (dimethyl sulfoxide).

  For all of the following examples, standard procedures known to those skilled in the art can be utilized. Unless otherwise specified, all temperatures are expressed in ° C. (degrees Centigrade). All procedures are performed at room temperature unless otherwise noted. The methods illustrated herein are intended to exemplify the applicable science through the use of specific examples, but do not dictate the scope of this disclosure.

(Example 1)
(General biological methods)
(Cell culture)
Leukemia cells or cell lines (HL-60, RSV411, k562, Jurkat, U937), lymphoma cells or cell lines (MDAY-D2), solid tumor cells or cell lines (PPC-1, HeLa, OVCAR-3, DU-145 , HT-29), and GM05757 human lung fibroblasts were cultured in RPMI 1640 medium. HepG2 hepatoma cells and MRC5 human lung fibroblasts were grown in Dulbecco's modified Eagle medium. OCI-M2, OCI-AML2, and NB4 leukemia cell lines and OPM2, KMS11, LP1, UTMC2, KSM18, and OCIMy5 myeloma cell lines were maintained in Iscove's modified Dulbecco medium. LF1 human lung fibroblasts were maintained in HAM medium. All media were supplemented with 10% fetal bovine serum, penicillin 100 μg / mL, and streptomycin 100 units / mL (all obtained from Hyclone, Logan, UT). These cells were incubated at 37 ° C. in a humidified atmosphere supplemented with 5% CO ₂ .

(Cell cycle)
Cells were harvested, washed with cold PBS, resuspended in 70% cold ethanol and incubated overnight at -20 ° C. Cells were then treated with DNase-free RNase (Invitrogen, Carlsbad, Calif.) 100 ng / mL for 30 minutes at 37 ° C., washed with cold PBS, and in PBS containing protease inhibitor (Sigma) 50 μg / mL. Floated again. DNA content was analyzed by flow cytometry (FACSCalibur; BD Biosciences, San Jose, CA).

(Example 2)
(Luciferase assay for anticancer activity)
The anticancer activity of ciclopirox was determined using a luciferase assay as described herein.

、及びリバースプライマー

を使用し、HeLaゲノムDNAから、完全長サバイビンプロモーター(開始ATGの-1059上流)を単離することにより調製した。次にサバイビンプロモーターを、GL4.20ホタルルシフェラーゼレポーターベクター(Promega社、マジソン、WI)へとサブクローニングした。クローンは、CEQ 8000 Genetic Analysis System(Beckman社、ミシサガ、ON、カナダ)を使用し、方向及び完全性について配列証明した。HeLa細胞は、リポフェクタミン(Invitrogen社、CA)を用いサバイビンプロモーター構築体単独又はベクター単独によりトランスフェクションし、安定したクローンをピューロマイシン(4μg/mL)(Sigma社)により選択した。こうして選択された安定したHeLa細胞を、シクロピロクスのその抗癌活性に関する試験に使用した。 For the luciferase assay, we used HeLa cells that stably overexpress the human survivin promoter driving firefly luciferase, which was first used as a forward primer

, And reverse primer

Was used to isolate the full-length survivin promoter (-1059 upstream of the starting ATG) from HeLa genomic DNA. The survivin promoter was then subcloned into the GL4.20 firefly luciferase reporter vector (Promega, Madison, Wis.). Clones were sequence verified for orientation and integrity using the CEQ 8000 Genetic Analysis System (Beckman, Mississauga, ON, Canada). HeLa cells were transfected with survivin promoter construct alone or vector alone using Lipofectamine (Invitrogen, CA), and stable clones were selected with puromycin (4 μg / mL) (Sigma). Stable HeLa cells thus selected were used for testing for the anticancer activity of ciclopirox.

  To determine anticancer activity, HeLa cells stably overexpressing the human survivin promoter driving firefly luciferase were treated with ciclopirox 5 μM for 24 hours. These HeLa cells (15,000 cells / well) were seeded in 96-well plates. After adherence to the plate, HeLa cells were treated with ciclopirox 5 μM (0.05% DMSO). After incubation for 24 hours, survivin promoter activity was assessed using a luciferase assay to assess inhibition of transactivation of the survivin promoter. At the time of measurement, the cell culture medium was removed from the 96-well plate, and 1 × Glo lysis buffer (Promega) was added to the plate. After 10 minutes of incubation, an equal volume of Bright-Glo luciferase substrate (Promega) was added and the luminescence signal was obtained with a 96-well Luminoskan luminescence plate reader (Thermo Fisher Scientific, Waltham, MA) with an integration time of 5 seconds. Detected.

  Ciclopirox was retested for reproducibility using a luciferase assay and also tested for viability. Cell viability was determined using the CellTiter96 aqueous non-radioactive (MTS) assay, where propidium iodide (PI) staining was used (Biovision, Mountain View, CA).

  Ciclopirox was further evaluated as an anticancer agent by treating leukemia cell lines with increasing concentrations of the compound for 72 hours. Cell viability was also measured by MTS assay. Cell death was assessed by detecting the presence of the sub-G1 peak by flow cytometry after cell staining with PI.

  Results were normalized and corrected for systematic errors using B scores (Gunter literature, J Biomol. Screen. 2003, 8, 624-633).

  Ciclopirox inhibited survivin transactivation by more than 60% while maintaining cell viability exceeding 90% at 24 hours after treatment. The effect of ciclopirox on survivin transactivation was confirmed in a dose response study.

(Example 3)
(Determination of survivin mRNA and protein expression levels in HeLa cells)
The level of survivin mRNA and protein expression in wild-type HeLa cells treated with ciclopirox was measured using quantitative real-time polymerase chain reaction (QRT-PCR) and immunoblotting to determine its anti-cancer activity.

リバース、

及び、GAPDH、フォワード、

リバース、

。
等量のcDNAを、調製したマスター混合物(SYBR Green PCRマスターミックス；Applied Biosystems社、フォスターシティ、CA)へ添加した。QRT-PCRを、ABI Prism 7700配列検出システム(Applied Biosystems社、フォスターシティ、CA)において行った。転写物の相対存在量を、増幅の閾値サイクル(CT)により表し、これは標的RNA/増幅される第一鎖cDNAの量に逆相関した。等量の後者に関して正規化するために、推定ハウスキーピング遺伝子GAPDHの転写物レベルをアッセイした。 For QRT-PCR, cDNA encoding survivin and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was amplified using the following primer pairs: survivin, forward,

reverse,

And GAPDH, forward,

reverse,

.
An equal amount of cDNA was added to the prepared master mix (SYBR Green PCR master mix; Applied Biosystems, Foster City, CA). QRT-PCR was performed on an ABI Prism 7700 sequence detection system (Applied Biosystems, Foster City, CA). The relative abundance of the transcript was represented by the threshold cycle of amplification (CT), which was inversely related to the amount of target RNA / first strand cDNA amplified. To normalize for an equal amount of the latter, transcript levels of the putative housekeeping gene GAPDH were assayed.

  Total cell lysates were prepared for immunoblotting. Cells were washed with phosphate-buffered saline pH 7.4 and lysis buffer (10 mM Tris, pH 7.4, 150 mM NaCl, 0.1% Triton X-) containing protease inhibitors (complete tablets; Roche, IN). 100, 0.5% sodium deoxycholate, and 5 mM EDTA). Cytoplasmic proteins by incubating the cells on ice for 15 minutes with cytoplasmic buffer (10 mM HEPES, 10 mM KCl, 0.1 mM EDTA, 0.1 mM EGTA, 0.1 mM EGTA, DTT 1 mM, NP40 0.65%, protease inhibitor, pH 7.4) After extraction and centrifugation at 10,000 g for 1 minute at 4 ° C., the nuclear extract was isolated. The pellet is resuspended in lysis buffer (10 mM Tris, pH 7.4, 150 mM NaCl, 0.1% Triton X-100, 0.5% sodium deoxycholate, 1.7% SDS, 5% glycerol and 5 mM EDTA) for 30 minutes, The mixture was then centrifuged at 4 ° C for 20 minutes at maximum speed. Protein concentration was measured by Bradford assay. An equal amount of protein was subjected to sodium dodecyl sulfate (SDS) -polyacrylamide gel and subsequently transferred to a polyvinylidene difluoride membrane. Polyclonal rabbit anti-human survivin antibody (1 μg / mL) (NOVUS), monoclonal mouse anti-human p53 antibody (0.5 μg / mL), polyclonal rabbit anti-human GR antibody (0.5 μg / mL) (both Probing with Santa Cruz Biotechnologies, CA); or with mouse anti-human GADPH antibody (Trevigen, Geysersburg, MD). Secondary antibodies (GE Healthcare, Chalfont St Giles, UK) are horseradish peroxidase-conjugated goat anti-mouse IgG antibodies (1: 10,000, v / v) and anti-rabbit antibodies (1: 5000, v / v). there were. Detection was performed by enhanced chemiluminescence (Pierce, Rockford, IL).

  Ciclopirox reduced survivin mRNA and protein expression in wild-type HeLa cells as assessed by QRT-PC and immunoblotting, respectively.

(Example 4)
(Leukemia stem cells)
Ciclopirox was tested for its ability to reduce the viability of TEX and M9-ENL1 cells. TEX cells and M9-ENL1 cells are derived from lineage-depleted human umbilical cord blood cells (Lin-CB) transduced by TLS-ERG or MLL-ENL oncogene, respectively, and hierarchical differentiation and bone marrow regeneration. It exhibits similar characteristics to leukemia stem cells such as proliferation. TEX cells and M9-ENL1 cells were treated with ciclopirox at a final concentration of 1 μM or 5 μM. At 72 hours after incubation, cell viability was measured by Alamar Blue assay.

Ciclopirox was able to reduce the viability of TEX cells and M9-ENL1 cells by at least 75% and LD ₅₀ was found to be 1.5 μM and 2.5 μM, respectively.

(Example 5)
(Mouse xenograft model)
A mouse xenograft model was used to evaluate the in vivo anticancer activity of ciclopirox.

Mouse xenograft models by intraperitoneal or subcutaneous injection of MDAY-D2 (MDAY) mouse leukemia cells (5 × 10 ⁵ ) into NOD / SCID mice (Ontario Cancer Institute, Toronto, ON); or OCI -AML2 (2 × 10 ⁶ cells), K562 cells (2 × 10 ⁶ cells), MDAY-D2, or U937 leukemia cells are inoculated subcutaneously into the flank of NOD-SCID mice (3.5 Gy) irradiated at sublethal dose To prepare.

When tumors reached a volume 200 mm ^3, to start the compound treatment, mice were randomized at this time, ciclopirox 25 mg / kg / day (treatment group) or buffer control (non-treatment group) with oral gavage Received for 5-7 days. Caliper measurements are taken twice weekly to estimate tumor volume (tumor length x width ² x 0.5236) (Pham et al., Mol. Cancer Ther. 2004, 3, 1239-1248), treatment group and non-treatment Differences were compared between groups. On the 8th day (MDAY-D2), 16th day (OCI-AML2), or 30th day (K562) after injection of the cells, the mice were sacrificed and the tumor volume and weight were measured. Compared to the buffer control, oral ciclopirox reduced tumor weight and volume in all three models. It was found that there was no gross organ toxicity or weight loss after treatment with ciclopirox.

  Alternatively, primary AML cells were injected intrafemorally into the right thigh of nude / NOD / SCID female mice irradiated below the lethal dose. Four weeks after injection, mice were treated with ciclopirox (20 mg / kg / day) for 5 days out of 7 days for 4 weeks. At the end of the experiment, the mice were sacrificed and the cells were flushed from the thigh. Engraftment of human cells to the bone marrow was assessed by enumerating the percentage of human CD45 cells using APC-Cy7-anti-CD45 antibody and flow cytometry. The engrafted cells were confirmed to be of leukemia origin due to the presence of human CD33 and the absence of CD19. Treatment with ciclopirox significantly reduced primary AML cell engraftment without gross organ toxicity or weight loss compared to mice treated with buffer alone.

(Example 6)
(Pharmacokinetics of ciclopirox)
The pharmacokinetic parameters of ciclopirox were determined in rats and dogs using [ ¹⁴ C] -cyclopirox olamine. Ciclopirox was orally administered to rats and dogs. In rats, ciclopirox was orally administered at a dose level of 1 mg / kg, C _max of 0.083 to 0.17 μg / mL was observed 0.25 hours after dosing, and t _1/2 was 6.8 to 7.6 hours. In dogs, ciclopirox was orally administered at a dose level of 15 mg / kg / day and a C _max of 2-7.5 μg / mL was observed within 1.5-2 hours. In a 90-day oral repeated dose study in dogs, the mean C _max was 3.9 μg / mL after 10 mg / kg / day of ciclopirox olamine dose.

  Presence of human CD33 and lack of CD19.

(Example 6)
(Cell proliferation assay and determination of IC ₅₀ )
(Adherent cells)
On day 0, cells were seeded into individual wells of 96-well tissue culture plates at 20,000 cells / well in 100 μL medium. The next day, compounds were diluted in 100 μL of medium to a total of 200 μL. Each concentration of compound was prepared at a 1000-fold concentration in DMSO (eg, compound was prepared at 20 mM in 100% DMSO for a final concentration of 20 μM in the assay). The compound was then diluted 1: 500 in the medium, 100 μL was added to each well, and the final concentration was 1: 1000 with 0.1% DMSO. Each concentration of compound was tested in triplicate. Cells were incubated at 37 ° C. with 5% CO ₂ . After 72 hours, 20 μL of CellTiter 96 Aqueous One Solution Cell Proliferation Assay (Promega) was added to each well. Cells were returned to the incubator and absorbance at 490 nm was measured after 2-3 hours. The concentration of compound that reduced the number of metabolically active cells by 50% was determined and reported as the IC ₅₀ . “Viability (%)” was determined by subtracting the mean background value (medium only) and expressed as a ratio to the mean value obtained from cells treated with DMSO alone.

(Floating cells)
The suspension cell assay was similar except that 40,000-60,000 cells were added to each well and the compound was added immediately after cell seeding.

  The foregoing examples are provided to provide those skilled in the art with a complete disclosure and description of how to make and use the claimed embodiments and limit the scope of what is disclosed herein. It is not intended to be. Modifications apparent to those skilled in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited herein are specifically and individually identified as being incorporated by reference herein for each such publication, patent, and patent application. As incorporated herein by reference.

Claims (49)

  A pharmaceutical composition for treating drug-resistant leukemia in a subject, comprising 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone or a pharmaceutically salt or solvate thereof, The pharmaceutical composition is used such that a therapeutically effective amount of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof, is administered to the subject. Wherein the drug resistant leukemia is resistant to cytarabine or vincristine.   The pharmaceutical composition according to claim 1, wherein the drug-resistant leukemia is drug-resistant acute leukemia.   The pharmaceutical composition according to claim 2, wherein the drug-resistant leukemia is drug-resistant ALL.   The pharmaceutical composition according to claim 2, wherein the drug-resistant leukemia is drug-resistant AML. Wherein the drug-resistant leukemia, Ru drug resistance chronic leukemia der, pharmaceutical composition of claim 1.   The pharmaceutical composition according to claim 5, wherein the drug-resistant leukemia is drug-resistant CLL.   6. The pharmaceutical composition according to claim 5, wherein the drug resistant leukemia is drug resistant CML. The pharmaceutical composition according to any one of claims 1 to 7, wherein the drug-resistant leukemia is resistant to cytarabine . Wherein the drug-resistant leukemia is resistant to to vincristine The pharmaceutical composition of any one of claims 1-8.   The pharmaceutical composition according to any one of claims 1 to 9, wherein the drug-resistant leukemia is Philadelphia positive.   The pharmaceutical composition according to any one of claims 1 to 10, wherein the drug-resistant leukemia has recurred or is refractory.   The pharmaceutical composition is used such that 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone or a pharmaceutical salt or solvate thereof is orally administered. The pharmaceutical composition according to any one of claims 1 to 11.   13. The pharmaceutical composition of claim 12, wherein the therapeutically effective amount is about 2, about 5, about 10, about 15, or about 20 mg / kg / day.   The pharmaceutical composition is characterized in that 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutical salt or solvate thereof is used for parenteral administration. The pharmaceutical composition according to any one of claims 1 to 11.   The pharmaceutical composition is used such that 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutical salt or solvate thereof, is administered intravenously. The pharmaceutical composition according to claim 14.   16. The pharmaceutical composition according to claim 14 or 15, wherein the therapeutically effective amount ranges from about 0.001 to about 20 mg / kg / day.   17. The pharmaceutical composition according to claim 16, wherein the therapeutically effective amount ranges from about 0.05 to about 0.95 mg / kg / day.   The pharmaceutical composition is used such that 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutical salt or solvate thereof, is administered intramuscularly. The pharmaceutical composition according to claim 14.   The pharmaceutical composition is used such that 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone or a pharmaceutical salt or solvate thereof is administered subcutaneously. The pharmaceutical composition according to claim 14.   The pharmaceutical composition is used such that 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutical salt or solvate thereof, is locally administered. The pharmaceutical composition according to any one of claims 1 to 11.   The pharmaceutical composition is 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutical salt or solvate thereof, once a day, twice a day, or 1 day. 21. The pharmaceutical composition according to any one of claims 1 to 20, characterized in that it is used three times for about 1 to about 26 weeks. The pharmaceutical composition is used in such a way that after administration, 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutical salt or solvate thereof, is administered for a drug holiday. The pharmaceutical composition according to claim 21, wherein   23. A pharmaceutical composition according to claim 22, wherein the drug holiday is 1, 2, 3, 4, 5, 6, or 7 days; 2, 3, or 4 weeks.   The subject has received anti-cancer therapy for drug-resistant leukemia prior to the administration of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutical salt or solvate thereof. 24. A pharmaceutical composition according to any one of claims 1 to 23, which has not been treated.   The subject has received anti-cancer therapy for drug-resistant leukemia prior to the administration of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutical salt or solvate thereof. 24. A pharmaceutical composition according to any one of claims 1 to 23 which is being treated.   A pharmaceutical composition for treating drug-resistant leukemia in a subject, comprising 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone or a pharmaceutically salt or solvate thereof, When the pharmaceutical composition is 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof, about 2, about 5, about 10, about Said pharmaceutical composition characterized in that it is used to be administered orally at a dose of 15, or about 20 mg / kg / day, said drug resistant leukemia being resistant to cytarabine or vincristine.   A pharmaceutical composition for treating drug-resistant leukemia in a subject, comprising 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone or a pharmaceutically salt or solvate thereof, The pharmaceutical composition is 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof, to the subject from about 0.001 to about 20 mg / kg / day. Said pharmaceutical composition, wherein the drug-resistant leukemia is resistant to cytarabine or vincristine, wherein the drug-resistant leukemia is used intravenously in a range of doses.   28. The pharmaceutical composition of claim 27, wherein the dose ranges from about 0.05 to 0.95 mg / kg / day.   A pharmaceutical composition for treating drug-resistant leukemia in a subject, comprising 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone or a pharmaceutically salt or solvate thereof, The pharmaceutical composition is 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof, in the steady state ranging from about 1 to about 20 μM. Characterized in that it is used to be administered in an amount sufficient to provide a plasma concentration of cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, wherein the drug resistant leukemia is cytarabine or vincristine Said pharmaceutical composition which is resistant to.   A pharmaceutical composition for treating drug-resistant leukemia in a subject, comprising 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone or a pharmaceutically salt or solvate thereof, The pharmaceutical composition is 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof, in the range of about 0.1 to about 50 μM 6-cyclohexyl-1 -Hydroxy-4-methyl-2 (1H) -pyridone is used to be administered in an amount sufficient to provide a maximum plasma concentration, wherein the drug resistant leukemia is against cytarabine or vincristine And said pharmaceutical composition is resistant.   A pharmaceutical composition for treating drug-resistant leukemia in a subject, comprising 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone or a pharmaceutically salt or solvate thereof, The pharmaceutical composition is 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutically salt or solvate thereof is 6-cyclohexyl-1-hydroxy-4-methyl-2 ( Plasma of 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone that ranges from about 1 to about 50 μM at steady state when two or more doses of 1H) -pyridone are administered Said pharmaceutical composition, characterized in that it is used to be administered in an amount sufficient to provide a concentration, said drug resistant leukemia being resistant to cytarabine or vincristine.   32. The pharmaceutical composition according to any one of claims 26 to 31, wherein the drug resistant leukemia is drug resistant acute leukemia.   33. The pharmaceutical composition of claim 32, wherein the drug resistant acute leukemia is drug resistant ALL.   33. The pharmaceutical composition of claim 32, wherein the drug resistant acute leukemia is drug resistant AML.   32. The pharmaceutical composition according to any one of claims 26 to 31, wherein the drug resistant leukemia is drug resistant chronic leukemia.   36. The pharmaceutical composition of claim 35, wherein the drug resistant chronic leukemia is a drug resistant CLL.   36. The pharmaceutical composition of claim 35, wherein the drug resistant chronic leukemia is drug resistant CML. 38. The pharmaceutical composition according to any one of claims 26 to 37, wherein the drug resistant leukemia is resistant to cytarabine . Wherein the drug-resistant leukemia is resistant to to vincristine The pharmaceutical composition of any one of claims 26 to 38.   40. The pharmaceutical composition according to any one of claims 26 to 39, wherein the drug resistant leukemia is Philadelphia positive.   41. The pharmaceutical composition according to any one of claims 26 to 40, wherein the drug resistant leukemia has relapsed or is refractory.   A pharmaceutical composition for inhibiting the growth of drug-resistant leukemia stem cells, comprising 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, or a pharmaceutical salt or solvate thereof. The pharmaceutical composition, wherein the drug-resistant leukemia stem cell is resistant to cytarabine or vincristine.   43. The pharmaceutical composition according to claim 42, wherein the drug-resistant leukemia stem cell is a drug-resistant acute leukemia stem cell.   44. The pharmaceutical composition according to claim 43, wherein the drug resistant leukemia stem cells are drug resistant ALL or AML stem cells.   43. The pharmaceutical composition according to claim 42, wherein the drug-resistant leukemia stem cell is a drug-resistant chronic leukemia stem cell.   46. The pharmaceutical composition according to claim 45, wherein the drug resistant leukemia stem cell is a drug resistant CLL or CML stem cell. 47. The pharmaceutical composition according to any one of claims 42 to 46, wherein the drug resistant leukemia stem cells are resistant to cytarabine . Wherein the drug-resistant leukemia stem cells are resistant to vincristine, a pharmaceutical composition of any one of claims 42 to 47.   49. The pharmaceutical composition according to any one of claims 42 to 48, wherein the drug resistant leukemia stem cells are Philadelphia positive.

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